Female Infertility Factors

Understanding Female Infertility Factors

Video: Diagnosing PCOS

With more than 30 years of experience, Dr. Laurence Jacobs with the Fertility Centers of Illinois, uses three different assessments to determine if a patient suffers from PCOS.

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Female infertility is a broad condition that can be caused by one or more factors. Determining the cause of female fertility problems is key to overcoming them, so each patient undergoes a thorough diagnostic testing process before beginning infertility treatment at our practice in the Chicago, Illinois area. Understanding what causes infertility not only makes it possible to effectively treat it, but also helps patients cope with their condition. Every obstacle to female fertility that we are able to recognize interferes with one or more of the following processes:


Age (Diminished Ovarian Reserve)

Female age is a critical factor in determining the chances for getting pregnant. Increased infertility with female aging is well-documented and very common in our society. Due to the societal trend of increased numbers of women who delay childbearing for educational/career goals, delayed marriages or second marriages, we now have a significant increase in age-related infertility. Women are born with all of the eggs they will ever have. The eggs are contained in 'egg sacs' called follicles. As women age, throughout life the supply of eggs (ovarian reserve) gradually declines over time until the eggs are essentially depleted at menopause. In general, egg quality and quantity start to decline slowly starting in the early 30s, and then much faster in the late 30s and early 40s. At any given time, the number of good eggs that remain is very dependent on the woman's age plus other factors, such as genetics and previous ovarian surgeries.

Despite significant advances in infertility treatments over the past two decades, age-related infertility remains as one of the most difficult challenges for Dr Jacobs and other reproductive endocrinologists (REs). Advancing age leads to a diminished 'ovarian reserve' (supply of eggs) ... resulting in a decrease in both oocyte (egg) quantity and quality. Poor egg quality results in poor embryo quality, which therefore reduces the chances for becoming pregnant successfully. In addition, as maternal age increases, the rate of miscarriage also increases substantially, as does the chance of fetal chromosomal abnormalities, such as Down syndrome.

A thorough evaluation of a woman’s current and future remaining egg supply can be determined with several of the diagnostic tests for ovarian reserve.

Age-related female infertility is best treated by in vitro fertilization, and in some cases by use of an egg donor.

Ovulation Disorders (including PCOS)

Irregular ovulation or a failure to ovulate is generally caused by a hormonal problem, although diminished ovarian reserve is also a potential factor in patients over the age of 35. Hormone problems due to abnormalities of various endocrine glands, such as the hypothalamus, pituitary, thyroid or adrenal, will often result in ovulation disorders. For this reason, a comprehensive diagnostic endocrine evaluation will be done by Dr Jacobs whenever an ovulation problem is documented using ovulation testing. Numerous endocrine conditions, such as hypothyroidism (underactive thyroid function) or hyperthyroidism (overactive thyroid function) can be successfully treated with medications, thus restoring normal ovulation.

Polycystic Ovarian Syndrome, PCOS, is the most common endocrine ovulation disorder and is closely linked with diabetes, obesity, and infertility. Women with PCOS either do not ovulate or ovulate irregularly.

What is PCOS?

Women with PCOS have irregular menstrual cycles and infertility because they usually don’t ovulate. Researchers have determined that most women with PCOS have an endocrine imbalance known as “insulin resistance” in which the body doesn’t handle insulin normally. Insulin is the hormone produced in the pancreas that lowers blood glucose levels. After eating a meal, blood glucose levels rise. The pancreas responds by releasing more insulin into the bloodstream. The insulin helps the liver, muscle and fat, store some of the energy as glucose and fat, thus keeping blood glucose levels in a normal range.

Women with insulin resistance may have normal blood glucose levels, but because the cells of their bodies are resistant to insulin, the body compensates by producing even higher levels of insulin to keep their blood glucose levels normal. The resulting higher insulin levels lead to more fat storage (obesity) and also disrupt proper ovarian hormone production (increased male hormone), thus preventing ovulation. Insulin resistance ultimately can produce all the symptoms of PCOS.

PCOS symptoms may include:

  • Irregular or absent periods
  • Infrequent ovulation or no ovulation
  • Hirsutism (excessive hair growth) of face, chest, or abdomen
  • Acne
  • Weight gain
  • Infertility

To learn how to make an accurate diagnosis of PCOS and exclude other endocrine conditions, see "Diagnostic testing to confirm PCOS" and "PCOS Awareness Screening Program."

Symptoms of PCOS, including ovulation disorders and infertility can often be improved or corrected through lifestyle changes that help reduce weight and balance hormone levels.

First and foremost, overweight women frequently have hormonal imbalances and abnormal endocrine function, which results in a disruption of regular ovulation. Polycystic ovarian syndrome (PCOS) is one specific type of endocrine condition that is generally associated with obesity. In addition, insulin resistance (a condition that can develop into type 2 diabetes) is a common problem for overweight or PCOS patients and further interferes with ovulation. A proper fertility diet meets the nutritional needs of the patient while supporting weight loss and preventing the insulin surges that result in the creation of additional body fat.

Laurence Jacobs, M.D., Director of the Fertility Center of Illinois PCOS ‘CENTER OF EXCELLENCE’ has found that weight loss, by as little as 5 to 10 percent, can normalize hormone function, cause ovulation to resume, and result in spontaneous pregnancy, as well as improved pregnancy rates with ovulation induction and IVF therapies.

For more information on infertility treatments for PCOS and other ovulation disorders, see the sections on fertility medications and In Vitro Fertilization (IVF).

Tubal Factors

The Fallopian tubes play a vital role in picking up an egg after ovulation, and then also transporting sperm to the egg, followed by transport of the fertilized egg (embryo) back to the uterine cavity. The Fallopian tubes may be damaged by infections or many other pelvic conditions. Pelvic inflammatory disease (PID), usually caused by Chlamydia and/or Gonorrhea, previous tubal surgery, ectopic pregnancy, ruptured appendix, endometriosis and ovarian surgery often leads to tubal adhesions and tubal damage. Pelvic inflammatory disease, often asymptomatic, is a major cause of tubal factor infertility and ectopic pregnancies.

If tubal blockage occurs only at the distal end, then the fluid secretions of the fallopian tube will be unable to drain out of the end of the tube. This resulting accumulation of fluid in the tube (hydrosalpinx) has a very negative effect on fertility, even when women utilize in vitro fertilization (IVF) for treatment. Women planning to do IVF need to have the hydrosalpinx removed by laparoscopy prior to doing IVF, in order to improve pregnancy success rates. For more information, go to the section on laparoscopic treatments.

With the exception of laparoscopic removal of a hydrosalpinx, tubal factor infertility is now rarely treated surgically. Occasionally, during laparoscopic surgery for endometriosis, pelvic and tubal adhesions (scar tissue) will be treated surgically. Instead of surgery, in vitro fertilization allows for ‘bypassing’ the tubes, resulting in excellent pregnancy rates for tubal factor infertility.

See the section on Uterine Cavity and Fallopian Tubes Diagnostic Testing to learn more about evaluation of the Fallopian tubes.

Uterine Factors

Abnormalities with the uterine cavity can result in infertility, as well as recurrent miscarriages. These include most commonly, uterine polyps, adhesions or submucous fibroids (protruding into uterine cavity). There can also be congenital anatomical conditions, such as a uterine septum or a bicornuate (double) uterus or a unicornuate uterus.

See the section on Uterine Cavity and Fallopian Tubes Diagnostic Testing to learn more about evaluation of the uterine cavity for infertility and recurrent miscarriages.

Infertility and/or recurrent miscarriages (habitual abortion) due to polyps, submucous fibroids (myomas), adhesions or a uterine septum can be successfully treated by hysteroscopic treatment.



What is endometriosis?

Endometriosis is a relatively common gynecological condition affecting women during their reproductive years. The cause of endometriosis remains unclear and controversial. Endometriosis is defined as the presence of endometrial tissue (cells making up the uterine lining of the uterine cavity), getting outside the uterus, and growing on the fallopian tubes, ovaries, bowel, bladder, and the pelvic tissue linings (peritoneum).

This endometrial tissue growing outside the uterus is affected by the woman’s monthly hormone changes, just like the endometrial tissue inside the uterine cavity. The endometrial tissue (both inside the uterus and outside) initially thickens during the early phases of the menstrual cycle but then sheds and bleeds during menstruation. This misplaced endometrial tissue implanting and growing on the tubes, ovaries, bladder, bowel and the lining within the peritoneal cavity, results in monthly ‘internal’ bleeding. Several reports in the medical literature suggest that endometriosis may be related to impairment or deficiencies in the immune system. The immune system reacts to the bleeding and tissue, often causing scar tissue (adhesions) to form. The endometrial implants and scar tissue often lead to adhesions and distortion of pelvic structures, moderate to severe pain if close to nerves, and infertility. However, the immune system’s response to endometriosis may also play a negative role in terms of proper egg fertilization in the tubes and/or implantation of embryos, even with In Vitro Fertilization (IVF).

Endometriosis Symptoms

Classical pain symptoms may include painful menstrual periods (dysmenorrhea), painful intercourse and intermittent pelvic pain throughout the month. Unfortunately, there is no clear correlation between the severity (stage) of endometriosis and the severity of the symptoms. Mild endometriosis (stages I & II) can occasionally cause considerable painful symptoms, while some women with moderate or severe stages of endometriosis (III & IV) may be relatively symptom-free. For this reason, it can occasionally be challenging to make the correct diagnosis.

How Can Endometriosis be Diagnosed?

Based on symptoms and ultrasound evidence of ovarian cysts (endometriomas) and/or blood tests (CA-125), one can be suspicious of endometriosis. However, laparoscopy surgery is the only definitive method to diagnose endometriosis and determine its severity, as well as identifying adhesions affecting the fallopian tubes.

How Does Endometriosis Cause Infertility?

Whether or not so-called "mild" endometriosis affects fertility has remained controversial, but it appears that any stage of endometriosis, even mild, can negatively affect a woman’s fertility for a variety of reasons. When compared with normally ovulating women of a similar age who do not have endometriosis, women with mild to moderate endometriosis are about three to four times less likely to have a successful pregnancy.

Endometriosis may adversely affect fertility in several different ways:

  1. Anatomical - Pelvic or Tubal Adhesions (Tubal Infertility)
    Endometriosis and scar tissue can have adverse effects on normal tubal function which then interferes with ‘egg pickup’. (Tubal infertility). It is easy to understand how adhesions can negatively impact a woman’s fertility if the tubes have problems picking up an egg. With this type of problem, the degree of infertility is directly proportional to the anatomical severity of the endometriosis and adhesions. This type of infertility can generally be overcome with laparoscopic surgery and/or medical manipulation - fertility medications & IUIs and/or In Vitro Fertilization.
  2. Diminished Ovarian Reserve (Reduce Egg Supplies)
    More advanced stages of endometriosis (stages III & IV) are associated with large ovarian cysts, called endometriomas, as well as more severe pelvic adhesions. The large invasively growing endometriomas may destroy much of the normal ovarian tissue. More importantly, women with these advanced stages of endometriosis have often needed multiple extensive surgeries due to chronic pelvic pain. Multiple ovarian surgeries can often lead to a considerable reduction in the number of eggs remaining, as well as decreased ovarian blood flow due to adhesions following the surgeries. If an infertility patient has endometriomas that are not symptomatic, Dr Jacobs will leave them alone so as to not compromise their ovarian reserve of eggs, in anticipation of doing in vitro fertilization (IVF).
  3. Toxic pelvic peritoneal factors (toxic pelvic environment)
    Reactionary types of autoimmunity may occur with medical conditions, such as endometriosis, where there is widespread tissue damage. Patients may have an ‘altered peritoneal environment’ due to an inflammatory reaction triggered by the tissue damage from the endometriosis. This inflammatory reaction in the pelvis may result in the production and release of ‘toxic substances’ and activation of specific white blood cells. In this situation, endometriosis results in the release of these local pelvic toxins & white blood cells that may interfere with the fertilization of eggs as the eggs pass through the pelvis from the ovary into the fallopian tube. In addition to the eggs being exposed to various pelvic inflammatory cells and toxins, sperm waiting in the tubes may also be adversely affected, leading to decreased fertilization potential. Some fertility experts believe that virtually all women with endometriosis have an underlying toxic peritoneal factor to some extent, which can interfere with normal fertilization and reduce fertility. This may explain why pregnancy rates are reduced more than 4 fold in women with even the mildest stages of endometriosis.

    Unfortunately, the use of fertility drugs with IUIs, and even surgery to remove some of the endometriotic tissue or tubal adhesions, will usually not be enough to overcome infertility due to a toxic pelvic peritoneal environment. In vitro fertilization (IVF) can usually bypass this problem of the toxic pelvic environment by transferring the embryo(s) directly into the uterine cavity.
  4. Autoimmune implantation dysfunction
    In some women, tissue damage from endometriosis may lead to alterations in cell membrane phospholipids, resulting in the ‘autoimmune’ production of antiphospholipid antibodies (APAs). This may occasionally result in the ‘activation’ of specialized immune cells in the uterine lining known as Natural Killer (NK) Cells and Cytotoxic Lymphocytes (CTL). This type of reaction is referred to as autoimmune implantation dysfunction. Some researchers claim that up to 1/3 of women with endometriosis (any stage) have these immune barriers to implantation. The autoimmune NK/CTL ‘activation’ results in a lethal reaction against the implanting embryo. These women may not be able to conceive with IVF until the underlying autoimmune implantation problem has been identified and treated with immunotherapy. For some women, could this be a cause of so-called ‘unexplained’ infertility or perhaps repeated IVF failures?

    Women with endometriosis may benefit from an evaluation for immunologic factors, such as antiphospholipid antibodies (APA) and Natural Killer cell activation. Several reports have demonstrated that women with endometriosis-related autoimmune implantation failure may benefit from Intralipid or IVIG treatments, as well as steroids or Heparin or Lovenox, if administered prior to an IVF embryo transfer, depending on their abnormality. Without treatment, these women are not as likely to conceive.

Intralipid Therapy

Evidence from both animal and human studies suggests that Intralipids administered intravenously may enhance implantation. Dr Jacobs advocates aggressive evaluation and treatment of ‘immunologic implantation dysfunction’ in women who have recurrent miscarriages or failed IVF treatments despite good embryo quality. In cases where there is documented abnormal Natural Killer (NK) cell activation, he often recommends the use of Intralipids to down regulate (deactivate) the NK cells.

How is it Used?

The method of administration is an IV infusion (a drip in your vein) of around 1-2 hours duration and requires that you are not allergic to soy or egg products, and also do not have a history of high cholesterol or liver disease. Intralipids are synthetic and made from 1.2% egg yolk phospholipids, 10% soybean oil, 2.25% glycerin and water. Intralipid therapy is virtually free of side effects. It is usually administered 4-7 days before embryo transfer or intrauterine insemination (IUI). Intralipids are re-administered 4-5 weeks following a positive pregnancy test, to keep the NK cells deactivated until the pregnancy can override the signals being sent by the immune system.

Dr Laurence Jacobs offers Intralipid treatments at his two Chicago area IVF centers (apparent IVF in Highland Park & FCI River North IVF in Chicago). Intralipid therapy may benefit women who have had recurrent miscarriages, multiple failed IVF implantations (despite good embryo quality) or multiple failed IUI cycles, by deactivating natural killer cells in a woman’s body which may prevent embryos from implanting and growing properly in the uterus.

Intralipids are far less expensive than Intravenous Immunoglobulin (IVIG) and initial studies show comparable efficacy for deactivation of natural killer cells and pregnancy rates. Intralipids are well tolerated by patients with few side effects and are created synthetically, unlike IVIG which is a blood derived product. Therefore Dr Jacobs believes it is also clinically safer to use.

Intralipids have a suppressive action on certain components of the mother's immune system, essentially safeguarding the embryo from the immune reactions which might otherwise result in implantation failure. Worldwide there is less clinical experience with Intralipids than with IVIG, but Dr Jacobs has used Intralipid therapy in his Chicago area practice for several years. Therefore, many women with endometriosis, or women who have suffered multiple IVF treatment/implantation failures and/or recurrent miscarriages, if found to have abnormal natural killer cell activation, may benefit from Intralipid therapy.

Implantation Failures

Most failures of implantation of an embryo following treatment are due to egg and/or sperm quality problems and/or genetic issues resulting in abnormal or poor quality embryos. However, even if an embryo looks ‘normal’ and is graded good or even perfect, it still may not result in a healthy baby. For example, in some cases where the egg may have excellent quality, but the sperm genetics (DNA) is poor, the egg may compensate for a genetically defective sperm, resulting in the embryo reaching blastocyst stage (day 5) and may even implant, but still not result in a good pregnancy.

Although most failed implantations may be due to poor embryo quality or abnormal embryo genetics, some good embryos may fail due to uterine factors and/or poor ‘endometrial receptivity’. Successful implantation is a complicated process involving embryonic attachment and subsequent invasion into the endometrium (uterine lining). It is a complex series of events involving several growth factors and cytokines (protein substances that are secreted by specific immune cells which carry signals locally between cells), as well as proper ‘communication’ between the embryo and the endometrium.

Uterine Anatomical Factors

Implantation failure resulting in infertility and/or early recurrent miscarriages (habitual abortion) due to polyps, submucous fibroids (myomas), adhesions or a uterine septum can often be resolved by hysteroscopic treatment. More serious permanent damage to the endometrium may occur after a sexually transmitted disease results in pelvic inflammatory disease-PID or post abortion related infection after a D&C. Asherman's syndrome refers to scar tissue that forms typically after a D&C is performed due to a miscarriage, or for surgical termination of a pregnancy (abortion). This adhesion formation leads to the development of intrauterine scars that can obliterate the cavity to varying degrees. In the most extreme circumstances, the whole cavity can be scarred and occluded. In many cases, the scar tissue can be removed during a surgical hysteroscopy. If the uterine cavity is damaged beyond repair, gestational surrogacy remains an option.

Thin Endometrial Lining

A very frustrating, and unresolved problem is the nonresponsive, thin endometrial lining. Most IVF studies suggest that a triple-layered endometrial lining with thickness of 7 mm is adequate and preferably over 9 mm thickness in order to maximize pregnancy rates. Successful pregnancies can sometimes be achieved with a lining of 6 mm or less, but the prognosis is poor.

A thin endometrial lining may be due to hormonal issues, such as estrogen production or absorption being too low. This problem can often be improved with vaginal estrogen supplementation or estradiol valearate intramuscular injections.

A thin uterine lining may be due to diminished or compromised uterine blood flow. Clotting disorders and/or abnormally increased immune activity, such as elevated natural killer (NK) cell activity, could increase microscopic clotting in the endometrial tissue, resulting in diminished uterine blood flow. See the section on autoimmune implantation dysfunction.

Many treatment modalities have been utilized in order to improve uterine blood flow, depending on the underlying cause, but results are often disappointing. Compromised uterine blood flow may be improved with acupuncture, low molecular weight heparin, such as Lovenox, and, potentially with vasodilating medication like Trental or vaginal Viagra (sildenafinil). A thin lining caused by poor blood flow due to ‘autoimmune implantation dysfunction’ may be treated with Intralipids. Vitamin E, L-arginine and a variety of supplements have also been shown to occasionally help lining growth.

Neupogen (Granulocyte-colony stimulating factor --GCSF) has been tried for implantation failure and thin uterine lining since these factors seem to play a role in signaling between the embryo and uterine lining. A few early trials in which GCSF was given by injection or intravenously to women, resulted in slightly increased pregnancy rates, but the numbers of patients in these studies were small. A few recent clinical trials evaluated direct intrauterine perfusion with GCSF. In normal IVF patients, GCSF did not improve endometrial thickness, implantation rates, or clinical pregnancy rates.

A thin uterine lining may occasionally be due to endometritis (inflammation of the lining) - usually due to a bacterial infection, such as chlamydia, or ureaplasma. Endometritis can be easily treated with antibiotics, especially if the bacteria can be successfully identified by cultures. Some inflammatory changes can also be identified by endometrial biopsy and a pathology report.

Endometrial "Scratching" for Failed IVF Implantation

For women who have repeatedly failed IVF despite good embryo quality, gentle endometrial injury by ‘scratching’ the lining several weeks prior to embryo transfer, may have a beneficial role in implantation and improve pregnancy rates.

How Can Endometrial Injury Help?

It seems that following endometrial injury with an endometrial biopsy instrument, such as a Pipelle, during the healing process numerous substances are secreted including growth factors and cytokines. Local injury of the endometrium produces an inflammatory reaction resulting in increased white blood cells (leukocytes such as macrophages) which secrete these growth factors and cytokines. These substances regulate blastocyst embryo implantation and placental development. Others have theorized that IVF patients who fail to implant despite good embryo quality may not be able to increase the expression of genes related to endometrial receptivity. Several studies have demonstrated that endometrial injury results in a markedly increased expression of a large variety of genes thought to play a role in the preparation of the endometrium for implantation.

Many recent studies have confirmed higher pregnancy success rates following endometrial scratching in patients who have previously failed IVF implantation.

Endometrial scratching techniques may not benefit those older women who fail IVF because of poor embryo quality and/or aneuploidy (abnormal genetic chromosome numbers). At the present time, the endometrial biopsy should probably be reserved just for those patients failing IVF despite good or excellent embryo quality, where uterine receptivity appears to be an underlying problem

The endometrial biopsy office procedure carries little risk (30 seconds of pain/discomfort and a minimal risk for infection). Dr Laurence Jacobs has been incorporating this technique in his infertility practice for his in vitro fertilization patients at both FCI Chicago River North IVF and Highland Park IVF (apparent IVF) since 2010.

The EmbryoScope & Eeva - Time-lapse photography and software

New Revolutionary Technologies - Help or Hype?

Dr Laurence Jacobs at Fertility Centers of Illinois (FCI), is using the latest technologies to try to improve pregnancy rates during in vitro fertilization (IVF) — the “EmbryoScope” and the “Eeva.” These two revolutionary technologies are designed to hopefully improve in vitro fertilization (IVF) outcomes by providing quantitative and objective information on the earliest stages of the embryo’s development, utilizing time-lapse photography and software, without manipulating or removing the embryos from the incubator. This may be especially helpful for those couples that have previously failed IVF or suffered from recurrent miscarriages. Fertility Centers of Illinois was the first IVF clinic in Illinois to offer this cutting-edge scientific application for monitoring embryo development.

For more information about this exciting technology, go to Dr Jacobs’ blog article The EmbryoScope and Eeva — Revolutionary Technologies May Improve IVF Success.

Watch the video demonstrating the time-lapse Eeva incubators:

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