IVF Question

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• “Empowering Choices: Embryo Banking vs. Egg Banking for Fertility Preservation“

It’s crucial for women to make informed decisions about preserving their fertility. Delaying trying to conceive, relying on egg freezing, or assuming the biological clock can be paused are misconceptions. As women age, egg quality declines, affecting the chance of a successful, healthy pregnancy.

Let’s break down the key points:

1. Age and Egg Quality: As women progress past their mid-thirties, the quality of their eggs declines rapidly. This impacts conception rates, leading to higher miscarriage and chromosomal abnormalities like Down syndrome.
2. Comparing Chances:

1. • At 30, the natural conception rate is around 15-20%, with a 10-15% miscarriage rate and a 1:1000 chance of Down syndrome.
   • At 45, natural conception drops to 1-2%, with a 50-60% miscarriage rate and a 1:40 chance of Down syndrome.

1. IVF and Age:

1. • IVF success rates are better at younger ages, with a 50-60% conception rate for 30-year-olds and a 3-5% chance for 45-year-olds.
   • However, IVF doesn’t eliminate the increased risk of miscarriage or chromosomal abnormalities as women age.

1. IVF Realities:

1. • The success of IVF dramatically decreases with age, making informed decisions crucial.

Preimplantation Genetic Screening (PGS)/Preimplantation Genetic Testing for aneuploidy (PGT-A) is a breakthrough in fertility treatment, aiding the selection of the most viable embryos for a successful pregnancy. By analyzing all chromosomes, it significantly boosts the success rates of IVF. PGS/PGT-A not only increases the chance of a healthy baby per embryo transfer but also reduces the risks of miscarriages and chromosomal birth defects, regardless of the woman’s age.

Who Benefits from PGS/PGT-A?

PGS/PGT-A) has revolutionized embryo evaluation, especially for those facing unexplained IVF failure, infertility, recurrent pregnancy loss (RPL), and older women with diminished ovarian reserve (DOR).

Empowering Older Women: Embryo Banking

PGS/PGT-A is especially beneficial for women over 39 years of age and those with DOR, as it allows the storage (banking) of healthy embryos over multiple cycles, countering the ticking biological clock.. Selective banking of PGS-normal embryos over multiple cycles is a game-changer. It minimizes the impact of age on egg quality, giving these women a chance to make the most of their remaining time to conceive a healthy baby.

Egg Freezing: Factors to Consider

Eggs are vulnerable cells, and freezing a single egg is less effective than freezing a multi-cellular embryo. Additionally, a significant portion of eggs (especially in older women) have chromosomal abnormalities. This makes egg freezing less efficient and  embryo freezing, far more successful, especially when selectively freezing PGS/PGT-A-normal blastocysts.

Choosing the Right Path

Importantly, considering the decline in reproductive potential with age, it’s essential for women and couples to explore their fertility options before the age of 35. An aggressive approach, like moving to assisted reproduction and IVF can significantly improve outcomes. For younger women (<35y) who have normal egg reserves, especially those who are not married,  have not as yet settled on la “permanent” male partner or a do not feel secure with their existing male partner fathering a child with them might preferentially choose egg freezing . Conversely,  women who are comfortable with a designated male partner, older women and those who have DOR might rather select embryo banking.

In the choice between egg and embryo freezing, caution is advised. Current methods for egg selection lack chromosomal analysis. Conversely the performance of PGSGT-A allows for identification of the healthiest embryos for subsequent FET..

Either way, “timing” is a very important consideration.

By understanding these options, you can make an informed decision to maximize your chances of a healthy, happy family. Remember, knowledge is power in the journey to parenthood.

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• ENDOMETRIOSIS AND INFERTILITY: A RATIONAL BASIS FOR TREATMENT.

Women who have endometriosis are much more likely to be infertile. There are several reasons for this:

• First, endometriosis is associated with the presence of toxins in peritoneal secretions. As sperm and egg(s) travel towards the fallopian tubes they are exposed to these toxins which compromise the fertilization process
• Second, in about 25 – 30% of cases, endometriosis is associated with ovulation dysfunction.
• Third, in its most severe form, the condition is associated with scarring and adhesions in the pelvis, resulting in damage to, or blockage of the fallopian tubes, thereby preventing the union of sperm and eggs.
• Fourth, endometriosis is associated with abnormalities of the woman’s immune system which interfere with the ability of the fertilized egg to attach (implant) to the uterine wall.

Until quite recently, we really had no clue as to how reproductive problems associated with endometriosis evolve. Recent medical research has helped shed light on the subject and offers promise with regard to the future treatment of infertility/ reproductive failure associated with this condition. A few examples of recent breakthroughs include the following:

Endometriosis appears to have a genetic (familial) component .In the future, the development of genetic markers might provide an important diagnostic tool.

Patients with endometriosis have immunologic abnormalities. The most significant of these involve the presence of harmful antibodies known as antiphospholipid antibodies (APA) are in the bloodstream of about 66 percent of women with endometriosis. In about half such cases (i.e., about 1/3 of all cases of endometriosis…regardless of severity) the immunologic implantation is profoundly aggravated by the presence of activated (i.e.  “toxic”) natural killer cells (Nka) and activated cytotoxic lymphocytes (CTLa) in the uterine lining (endometrium). These NKa/CTLa attack the invading trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in death of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or even an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini miscarriages”.

Endometriosis often goes unnoticed for many years. Such patients are frequently erroneously labeled as having “unexplained infertility”, until the diagnosis is finally clinched through direct visualization of the lesions at the time of laparoscopy or laparoscopy. Not surprisingly, many patients with so called “unexplained” infertility, if followed for a number of years, will ultimately reveal endometriosis.

Advanced Endometriosis: In its most advanced stage, anatomical disfiguration is causally linked to infertility. In such cases, inspection at laparoscopy or laparoscopy will usually reveal severe pelvic adhesions, scarring and “chocolate cysts”. However, the quality of life of patients with advanced endometriosis is usually so severely compromised by pain and discomfort, that having a baby is often low on the priority list. Accordingly, such patients are usually often more interested in relatively radical medical and surgical treatment options (might preclude a subsequent pregnancy), such as removal of ovaries, fallopian pubis and even the uterus, as a means of alleviating suffering.

Moderately Severe Endometriosis. These patients have a modest amount of scarring/ adhesions and endometriotic deposits which are usually detected on the ovaries, fallopian tubes, bladder surface and low in the pelvis, behind the uterus. In such cases, the fallopian tubes are usually opened and functional.

Mild Endometriosis: These patients who at laparoscopy or laparotomy are found to have a few visible e3ndometrial “implants” but minimal distortion of pelvic anatomy are often erroneously labeled as having “unexplained” infertility. To hold that the there can only infertility can only be attributed to endometriosis if significant anatomical disease can be identified, is to ignore the fact that, biochemical, hormonal and immunological factors profoundly impact fertility. Failure to recognize this salient fact continues to play havoc with the hopes and dreams of many infertile endometriosis patients.

Endometriotic implants produce a toxic “peritoneal factor”

As mentioned above, toxins that impair fertilization are present in the peritoneal secretions of most patients with endometriosis. Impaired fertilization is a feature of endometriosis regardless of its severity. This explains why women with endometriosis three times are less likely to conceive per month of trying and why controlled ovarian stimulation with fertility drugs and/or procedures such as intrauterine insemination probably do not increase the chances of pregnancy over no treatment at all. It also explains why in vitro fertilization (which relies upon removing eggs through aspiration of the ovarian follicles before they can be affected by peritoneal toxins), by bypassing this handicap improves pregnancy rates dramatically and accordingly is the treatment of choice for most endometriosis patients with infertility.

Ovarian Endometriomas

 Advanced endometriosis is often associated with ovarian cysts (endometriomas/chocolate cysts) that are filled with altered blood and can be large and multiple.  When these are sizable (>1cm) they can activate surrounding ovarian connective tissue causing production of excessive male hormones (androgens) such as testosterone and androstenedione. Excessive ovarian androgens can compromise egg development in the affected ovary(ies) resulting in an increased likelihood of numerical chromosomal abnormalities (aneuploidy) and reduced egg/embryo competency”. In my opinion large ovarian endometriomas need to be removed surgically or rough sclerotherapy before embarking on IVF.

The “immunologic connection”

More than two thirds of patients with endometriosis have APA’s in their blood. These antibodies, given certain conditions, are capable of attacking the embryo and preventing implantation. There are at least 21 varieties of APA. Treatment requires prior and specific identification of all 21 sub-types and their gammaglobulin isotypes. Unfortunately, only a handful of Laboratories in the United States are capable of adequately testing for APAs. But it is probably not APAs that cause infertility in endometriosis patients. Rather it is the coexistence activated NK cells (Nka) and (to a lesser extent) activated T-cells (cytotoxic lymphocytes-CTL)that attack the early embryo’s root system as soon as it tries to attach to the uterine wall that causes the problem. The presence of APAs probably represents a marker which identifies those endometriosis patients who have immunologic problems requiring immunotherapy (approximately 30% of women with endometriosis (regardless of its severity) test positive for Nka cells). Optimal treatment is predicated upon an accurate diagnosis (see below).

How endometriosis CAN BE Diagnosed:

Endometriosis should be suspected when symptoms such as painful menstruation (dysmenorrhea), Pain with deep penetration with intercourse (dyspareunia and painful ovulation occur in women during the 2^nd half of their reproductive lives. The diagnosis is even more probable when there is associated infertility or recurrent pregnancy (RPL). Digital pelvic examination tends to be painful because of endometriotic deposits behind the cervix or adjacent to the uterus, which is often in fixed retroversion (tilted backwards and fixed in this position because of adhesions). Sometimes the ovaries are enlarged because of c cysts filled with decomposed blood (endometriotic or “chocolate” cysts).

Ultrasound examination is usually not helpful in diagnosing early endometriosis. However, in more severe cases, ovarian endometriomas have a characteristic appearance by ultrasound examination and can be diagnosed this way.

A new method , known as the BCL-6 (or Receptiva) test done on an endometrial biopsy sample, if positive is highly suggestive (but not absolutely diagnostic) of underlying endometriosis and might be worth doing in cases where the diagnosis is unclear and in cases of “unexplained infertility which is often due to undiagnosed mild to moderately sever endometriosis.

In the final analysis, the diagnosis of endometriosis can only be confirmed through direct visualization of endometrial deposits at the time of pelvic surgery (laparoscopy / laparotomy) or through histopathologic microscopic analysis of affected tissue.

Note: Endometriosis can be the master of disguise. Many women with mild disease are often asymptomatic , presenting with so called “unexplained infertility”. If the endometriosis is at a very early stage, even attempted visualization (at surgery) will often fail to identify the condition. Such women, will often, upon repeat laparoscopy, reveal the condition.

How should infertility associated with endometriosis be managed?

 The following basic concepts apply to management of endometriosis-related infertility:

• Ovulation induction with/without intrauterine insemination: Toxins in the peritoneal secretions of women with endometriosis exert a negative effect on fertilization potential regardless of how sperm reaches the fallopian tubes. It follows that intrauterine insemination will not improve the chances of pregnancy (over no treatment at all) in women with endometriosis.

• Pelvic Surgery aimed at restoring the anatomical integrity of the fallopian tubes does not counter the negative influence of toxic peritoneal factors that inherently reduce the chances of conception in women with endometriosis approximately three-fold. Nor does it address the immunologic dysfunction commonly associated with this condition. Pelvic surgery is relatively contraindicated for the treatment of infertility associated with endometriosis, when the woman is more than 35 years of age. With the pre-menopause approaching, such women do not have the time to waste on such less efficacious alternatives. In contrast, younger women who have time on their side might consider surgery as a viable option. Sizeable ovarian endometriomas should in my opinion, be removed in their entirety. Aspirating the content of such lesions is not adequate as they will return in time.

• In Vitro Fertilization (IVF): Not all women who have endometriosis require IVF! However, this treatment is in my opinion, advisable in the following circumstances:

• women who have advanced endometriosis
• where surgery and prior  treatment with fertility agents and/or IUI has proven to be unsuccessful.
• Women older than 35 years and those with   diminished ovarian reserve-DOR regardless of their age)) and women with endometriosis (regardless of age)
• Women with endometriosis (regardless of its severity who have an  IID (see below)

• The role of selective immunotherapy: In about 33% of cases, endometriosis, (regardless of its severity) is associated with an immunologic implantation dysfunction (IID) linked to activation of uterine natural killer cells (NKa), cytotoxic uterine lymphocytes (CTLa) and to a much lesser extent to APA.  This is diagnosed by testing the woman’s blood for APA and for NKa using the K-562 target cell test. NKa and CTLa activation  can also be determined by endometrial biopsy for cytokine analysis. NKa/CTLa  attack the embryo’s  invading trophoblast cells (developing “root system”) as soon as begins to  attach to the uterine lining. In most cases, this results in death of the embryo even before the pregnancy is diagnosed. Sometimes it presents as a chemical pregnancy or as an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, actually experience repeated undetected “mini miscarriages”.

Women who harbor APA’s often experience improved IVF birth rates when heparinoids (Clexane/Lovenox) are administered from the onset of ovarian stimulation with gonadotropins until the 10th week of pregnancy. NKa is treated with a combination of Intralipid (IL) and steroid therapy: Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid.IL is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid) , 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%)  and water (76.5%).IL exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating NKa.

While the exact cause of endometriosis remains an enigma, it is now apparent that immunologic dysfunction is likely to be a significant feature of this disease. Whether immunopathology is causally linked to this condition or whether it occurs in response to endometriosis is unknown. Regardless, the underlying immunologic disorder adversely impacts on implantation of the embryo/early conceptus. It is possible, through thorough and meticulous evaluation, to quantify, typify and thereupon, selectively treat the underlying IID.. In so doing, IVF pregnancy rates can be significantly improved.

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