In order to conceive, ideally patients have one young egg released every month. Infertility that is related to the female’s eggs can be divided into two categories. The first category is whether or not the egg is being ovulated and the second is related to the quantity and quality of the egg that is determined by a female’s age. If a woman does not have a regular menstrual period coming every 24-35 days, this can be related to infrequent or absent ovulation. This results in infertility because an egg is not available for fertilization. Women who report having a menstrual period every month and have symptoms such as breast tenderness prior to their monthly period are usually ovulating an egg. If women are not having a regular period and it is deemed that they are not ovulating an egg, an evaluation is necessary to determine the cause.
Five of the main reasons why ovulation does not occur regularly include polycystic ovarian syndrome (PCOS), primary ovarian insufficiency (POI), thryoid disease, high prolactin levels, and hypothalamic dysfunction. The diagnosis of polycystic ovarian syndrome (PCOS) requires two of the following: menstrual irregularities, androgen excess, and polycystic appearing ovaries on ultrasound. This condition affects 5-8% of reproductive age women. Primary ovarian insufficiency is when the number of eggs in the ovaries is very low and as a result the patient has irregular periods and symptoms of hot flashes. In order to meet criteria for this diagnosis the patient must be under 40 years of age. If a patient has either low or high thryoid levels or has high prolactin, a milk producing hormone released by the brain, this can lead to irregular ovulation. Lastly, a patient can have a condition called hypothalamic dysfunction. This can result if a patient is susceptible to certain stressors causing their brain to release subnormal amounts of the hormones necessary for ovulation.
On average, a woman will ovulate 400 times during her lifetime. By the age of 50-51, she will deplete her stores of eggs and therefore menopause ensues.
The other cause of infertility related to the egg is the actual number and quality of the eggs. Even if a patient is ovulating regularly each month, they still may have difficulties conceiving. In order to understand this cause, it is important to understand a little bit more about normal ovarian physiology. As a female, we have the most eggs we will ever have when we are in our mother’s uterus, around five to six million. By the time we are born, there are around two million. At puberty the number is down to a couple hundred thousand, at age 37-38 around 25,000, and by menopause we essentially have no functioning eggs remaining. If ovulation is normal, each month one of our eggs is ovulated and the rest that are there die off. Therefore we have an exponential decline in the number of eggs. Additionally, because the eggs have been around since before we were born, they do not divide well leading to problems with the number of chromosomes in the egg itself. If the number or chromosomes in the egg is not correct, this can lead to problems with the embryo implanting in the uterus and an increased risk of miscarriage.
We determine if a patient is ovulating based on their menstrual cycle history and testing their progesterone in the second half of their menstrual cycle. In order to evaluate the quantity of eggs in patient’s ovaries we test hormone levels called estradiol and follicle stimulating hormone (F.S.H.) on day two or three of the patient’s menstrual cycle.
The uterus is where the embryo implants and grows in order to become a baby. It is made up of muscular tissue called the myometrium and the lining tissue, where the embryo implants, called the endometrium. The uterus is connected to the vagina via the cervix and it is connected to the inside of the pelvis via the fallopian tubes. It is these tubes that the egg travels through after it is released from the ovary. Many conditions can affect the uterus itself and therefore can make it more difficult for implantation of the embryo to occur. Fibroids, an overgrowth of the muscle tissue in the uterus, can interfere with implantation and the growth of the embryo depending on their location and size. Endometrial polyps, an overgrowth of the endometrial tissue of the uterus, can also impede implantation and the growth of an embryo. Additionally, scarring inside of the uterus, Ashermans Syndrome, as well as can some uterine malformations like uterine septums, can lead to problems with implantation and embryo growth.
We determine if the inside of the uterine cavity is normal by performing a test called a hysterosalpingogram (HSG) or a saline sonography. During these tests, a dye is instilled into the uterus at the same time imaging is performed in order to see if there are areas of the inside of the uterus that do not fill up with the dye.
The fallopian tube function is to pick up the egg from the surface of the ovary upon ovulation. It is here that the sperm and egg meet and fertilization occurs. Once fertilization occurs, the resultant embryo travels along the tube for the next couple of days prior to being released into the uterus. The internal lining of the fallopian tube contains delicate hair like projections that are instrumental in facilitating the transport of the sperm, egg, and embryo through the inside of the tube. If a patient has a tube or tubes that are damaged or blocked, the sperm and the egg are not able to meet and fertilization cannot occur in the body. If fertilization does occur but the tube is damaged, it may not be able to transport the embryo to the uterus. One cause of tubal damage is secondary to sexually transmitted diseases such as Gonorrhea and/or Chlamydia. These infections, if undetected and left untreated, can permanently damage the tube’s delicate lining and if they cause scar tissue it can cause tubal blockage. Another cause of tubal damage is secondary to surgeries that take place in the pelvis such as when ovarian cysts are removed or when a patient has surgery for appendicitis. Additionally, endometriosis can cause scarring and tubal damage and blockage.
We determine if the tubes are patent by performing a test called a hysterosalpingogram (HSG). During this test, dye is instilled into the uterus and the tubes at the same time imaging is performed in order to see if the tubes fill up with the dye and ultimately spill the dye liquid into the pelvis.
This is a condition where the tissue that is similar to the tissue that lines the inside of the uterus implants outside of the uterus onto the ovaries, tubes, and other areas in the pelvis. This tissue can secrete certain chemicals that may be harmful to the egg or sperm and/or can cause scarring that interferes with normal anatomy causing problems with the normal pick up of the egg by the fallopian tubes. We do not know the exact cause of this disease but we do know that patients who have this diagnosis do have a decreased fertility potential compared to those who do not.
We typically make the diagnosis of endometriosis based on a patient’s history and physical examination. However, the only way to diagnose this condition for certain is to perform an operation and see if endometriosis is present.
Ovarian DiseaseThe basis of reproduction is the presence of egg and sperm. Therefore, it is natural to look at the ovaries as the initial step in the investigation of the female partner.
There are a multitude of conditions or diseases that affect the ovaries and cause infertility. In this section, we will review conditions that are most commonly involved in female infertility.
Ovulation DisordersBackground: The ovulatory cycle in women starts with follicular recruitment. The ovary, which is endowed with a set complement of eggs well before birth, is the organ responsible for ovulation. Inside the ovaries, hundreds of small “preantral follicles” exists, that upon adequate signals from a small gland in the brain called “the pituitary gland”, will start growing just before the initiation of menstruation (Click for Figure 4). Of all the follicles that start growing, only one usually will reach maturity and ovulate. The rest will die-off in the process.
A hormone called Follicle Stimulating Hormone or FSH is secreted into the blood by the pituitary gland. Its role is to reach the ovaries and order a complement of preantral follicles to start growing. Another hormone called, Luteinizing Hormone or LH, will also assist in this process. As these follicles grow, one of them becomes Dominant. It starts secreting certain chemicals that will cause the others to die-off or stop from growing. Roughly 13-14 days after the start of the menstrual cycle, this dominant follicle will be ready to release its egg. This constitutes ovulation. (Click for Figure 2) Under the influence of a surge of the LH hormone by the pituitary gland, the dominant follicle will rupture and release the egg to the surface of the ovary where it will hopefully be picked-up by the fallopian tube and be transported to the tubal lumen where it will await for the sperm.
The egg, which is present inside the follicle also matures as the follicle is growing. (Click for Figure 5 ) As the egg and follicle mature, the granulose cells, which line the cavity of the follicle, start secreting a hormone called Estrogen, which can be measured with a simple blood test. The level of this hormone can provide us with valuable information regarding the number of eggs growing and their maturation stage.
A typical menstrual cycle can be divided into two halves (Click for Figure 6): The first half, from the start of the menstrual bleed up to day 14, is called the follicular phase and is the time during which the dominant follicle reaches maturity and is released at mid-cycle or day 14. This half of the menstrual cycle can be variable, i.e. it can last from 7-14 days. The second half of the menstrual cycle, called the luteal or secretory phase, lasts 14 days and is usually fairly constant. During this time, the follicle that released the egg, now called the Corpus Luteum, secretes the hormone Progesterone, which is responsible for preparing the uterine lining for implantation and if pregnancy occurs, to sustain it for the first 6-7 weeks of gestation, at which point the placenta takes over. Roughly 14 days after ovulation or on cycle day 28 (in women who get periods every 28 days), the Corpus Luteum will stop producing Progesterone unless it is rescued by another hormone called Human Chorionic Gonadotropin hormone (HCG), secreted by the growing placenta.
The first piece of history that a physician needs to take from the female partner, is regarding the pattern of the patient’s periods. If the history confirms the presence of regular cycles, the physician can then be assured that the patient is producing an egg every month. One way to confirm ovulation is by performing a blood hormone level for Progesterone. The test needs to be done a week after expected ovulation. A level over 3 ng/dl confirms ovulation. Another way is by doing serial pelvic ultrasound examinations to visualize the maturing follicle (with the egg in it) and confirm its rupture few days later.
A woman will on average, ovulate 400 times during her lifetime. By the age of 50-51, she will deplete her stores of eggs and therefore menopause ensues. Unfortunately, several years before menopause or during the perimenopausal years, a woman will start having erratic ovulations and therefore irregular periods. This can be accompanied with symptoms of hot flushes, which is secondary to a decline in estrogen levels, because of the lack of regular egg production. Another instance of abnormal ovulation is the period immediately after puberty. For several months women may have irregular menstrual cycles because of erratic ovulation.
Problems with ovulation are the most common causes of female infertility. These abnormalities can range from the occasional lack of ovulation and irregular periods to the total absence of ovulation with the resultant lack of any periods or amenorrhea.
There are a variety of conditions that can be associated with abnormal ovulation. Some of these causes are:
Abnormalities Related To WeightThe amount of body fat plays an important role in the normal regulation of a woman’s menstrual cycle. A significant decline can result in the total absence of normal periods or more commonly in the occurrence of irregular periods due to abnormal ovulation. This is why many athletes, such as marathon runners or ballet dancers suffer from infertility.
Studies have also demonstrated that overweight women have a higher chance of having anovulatory infertility especially when their BMI is greater than 27 kg/m2.
Diseases Of The BrainSince the hormones governing the ovaries are released by areas of the brain called the hypothalamus and the pituitary gland, diseases affecting these areas such as tumors can cause abnormalities of ovulation. One such tumor is called a Prolactinoma that affects the pituitary gland.
Genetic CausesThere are certain genetic conditions associated with abnormalities of chromosomes than can result in female infertility due to anovulation. One such common condition is a disease called Turner’s syndrome. These women lack one of their X chromosomes and are born with “streak ovaries”, which are not functional and cannot produce eggs.
Some women suffer from a condition termed Premature Ovarian Failure. In these cases, due to an unknown genetic cause, the ovaries stop from functioning usually before the age of 40, which in turn results in amenorrhea or the absence of periods. The reason for the rapid depletion of eggs in these patients is not very clear.
Polycystic Ovarian DiseaseAnother common cause of female infertility is the condition referred to Polycystic Ovarian Disease or Syndrome (PCO). Many such patients also have other signs of the disease such as excess hair growth, especially on the face, inner thighs and lower abdomen. Some also suffer from excess body weight. There are other conditions associated with abnormal ovulation and the specialist will perform certain hormonal testing to try and elucidate the possible cause.
PCOS is one of the most common causes of abnormal ovulation and infertility in women. The exact cause of the disease is not well known but recent studies have demonstrated a clear link between PCO and Insulin resistance. Hence the link between PCO and Diabetes. Women with PCO suffer from an abnormal Insulin metabolism which leads to higher levels of this hormone in blood to keep normal blood sugar levels. The higher Insulin level leads to increase male hormones which in turn lead to a disturbance of the whole ovulatory process and in some patients to hirsutism or excess body hair. It is also thought that some patients with PCO have poor quality eggs secondary to exposure to elevated male hormone levels and some suffer from an increased miscarriage rate. Some reports actually show a doubling of the rate.
The Insulin is also the reason that PCO patients are at an increased risk of Diabetes later in life and should have periodic testing every 1-2 years to check for it.
Treatment of PCO involves ovulation induction. Initially the simpler oral medications are used such as Clomiphene citrate or Letrozole. In cases of failure, more aggressive treatment is used with injectable forms of ovulation inducing medications. For some, In Vitro Fertilization is needed as the ultimate therapy.
Click To View “Understanding PCOS” with Dr. Kari Sproul
The Age Factor
It is impossible to review infertility and avoid consideration of the effects of age on fertility or egg quality. Many women are delaying childbearing into their late 30s and 40s, which has resulted in a significant increase in infertility due to the “Age Factor”. There is no doubt that fecundity declines with a woman’s age.
Click To View “Understanding Pre-Mature Ovarian Failure” with Dr Kari Sproul
Many studies, including IVF success rates, demonstrate a marked drop in pregnancy rates as women get into their late thirties. It has been shown for instance, that the chance of a 20 year old woman conceiving after one month of exposure is around 30%. While, at 30 years this rate drops to 20% per month and at 40 it is 10% per month. At 45, there is less than 2-3% chance that a woman will conceive on her own after trying for one cycle. Parallel to this, the miscarriage rate increases from 10% at the age of 20 to 40% at the age of 45.The reason behind this phenomenon lies in the fact that egg quality deteriorates with time, which in turn translates in lower pregnancy rates. Unlike men, women are born with a set number of eggs which they use up over the lifespan of their reproductive years. Testicles in men on the other hand, generate a fresh batch of sperm every 70-80 days, hence the minimal effect of age on their fertility potential. With time, the complement of eggs dormant in the ovaries will deteriorate, hence the lower fecundity rate. A direct corollary to this is the increased risk of chromosomal anomalies in infants born to older women. This is why it is recommended that women over 34 have an amniocentesis performed at 16-17 weeks of gestation to rule-out a chromosomally abnormal fetus.
Studies also demonstrate that at or around the age of 37, there is an accelerated loss in the quality and number of eggs. Hence an acute drop in pregnancy rates in women older than 37. One of the most common causes of infertility in this age group is accelerated ovarian aging. A term used to imply that the ovaries at a certain age is behaving as if they are older. It is imperative that every woman seeking help for infertility be tested for her ovarian reserve (see Testing).
Surgical DamageIn some cases, the ovaries can be damaged during incidental surgical procedures.
One of these common procedures is the removal of ovarian cysts. The surgery involves cutting into the ovaries to remove these cysts, which in turn can interfere with the integrity of the blood supply to the organ and lead to loss of perfectly healthy follicles containing eggs.
Another surgical procedure implicated with harming the ovaries is “Ovarian Drilling”. In this procedure, small holes are made through the ovarian tissue with a cautery (basically burning the tissue) in patients with PCO to lower male hormone levels which are elevated in these patients. This damage, if extensive, can actually destroy enough ovarian tissue to cause permanent loss of eggs.
Finally, other commonly performed surgeries that can potentially harm normal ovaries include surgeries on the tubes such as for ectopic pregnancies or surgical treatment of endometriosis when the disease has affected the ovaries.
Tubal DiseaseThe Fallopian tubes are the two “bridges” that connect the uterus to the ovaries. They are instrumental in the normal fertilization process that takes place in the distal area of the tube. (Click for Figure 8). The end of the Fallopian tube, the fimbria, is made of finger-like projections that swipe over the surface of the ovary and transfer the ovulated egg into its lumen. Any damage to the fimbriae will result in the inability of the tube to perform this function.
Once inside the tube, the ovulated egg awaits the arrival of the sperm from the other uterine side. The lumen of the Fallopian tube has a lining of very specialized cells with hair-like projections at their surfaces, which help nourish the egg and sperm and help in the fertilization process. After successful fertilization, the newly formed zygote is then transferred to the lumen of the uterus with the help of these tubal ciliated cells. Any damage to these latter, will also result in failure of fertilization or transport often leading to ectopic pregnancies in the tube. Obviously if the tubes are blocked or absent, then the sperm will never reach the egg or the egg will never be picked up by the tube and infertility ensues.
There are many conditions that can result in tubal damage and infertility:
Pelvic InfectionsThe most common cause of tubal disease is pelvic infection secondary to sexually transmitted diseases with Gonorrhea and/or Chlamydia. The infections typically affect young sexually active women and sometimes go unnoticed by the individual. Often the patient will have a vaginal discharge with pelvic pain for few days before she seeks help. If caught in time, treatment with antibiotics will clear the disease without long term sequelae. In cases where treatment is not rendered, the bacteria can travel through the uterus and involve the tubes. The disease is called Pelvic Inflammatory Disease (PID) and can be very serious if untreated immediately.
There are different levels of damage that can occur in these cases. In mild cases, only the lumen of the tube is affected but damage to the ciliated epithelium or lining can still result in infertility or ectopic pregnancy. In the more serious cases, the fimbria are affected, the end of the tubes are clubbed or blocked with fluid accumulation in the proximal part of the tube called hydrosalpynx. Infertility is the obvious outcome as the tubes will not be able to pick up the egg. The disease does not necessarily affect both sides equally in some patients and it is possible to have one side blocked while the other is still patent. However in such cases, the patent tube is often non-functional because of damage to the luminal cells.
There are several possible side effects or complications from tubal disease. The dilated or swollen tube can cause pelvic pain. A patent but damaged tube is the most common cause for ectopic pregnancies. In these cases, the fertilized zygote gets “stuck” inside the tube on its way back to the uterus and continues growing to eventually cause pain and rupture with bleeding. An ectopic pregnancy is a medical emergency in need of immediate attention.
For treatment of tubal disease please refer to the “Treatment” section of this website.
EndometriosisEndometriosis remains one of the most common and puzzling gynecological disorders in women. It is the presence of tissue similar to the lining of the uterus or endometrium, outside the uterus, on the tubes, ovaries, bowels and the peritoneum or lining of abdomen. Hereditary factors confer a tendency for development of endometriosis and recent studies have suggested that the immune system may be involved. The exact cause however is not yet established.
The peak incidence is in the third and fourth decade of life, but this condition may be seen at any time in reproductive age women. It is thought that 15% of infertile patients have endometriosis.
Endometriosis goes through different stages. In stage 1 disease, small implants are present inside the pelvis outside the confines of the uterus without any anatomical interference of egg pick-up. In stage 4 disease, the ovaries and tubes can be involved with extensive scarring and cysts and therefore direct interference would be present with the normal functionality of the tubes and ovaries.
Endometriosis should always be considered a possibility in infertile patients, particularly in the presence of a positive family history or other symptoms suggestive of the disease. Premenstrual pelvic pain, worsening pain with periods and intercourse are the most common symptoms of endometriosis, although the degree of pelvic pain seems unrelated to the severity of the disease process.
The treatment of endometriosis could be difficult and should be directed towards the problem. If pain is the main complaint, surgical treatment with laparoscopy with “fulguration” or burning of the endometriosis is often very successful. Even the presenting complaint is that of infertility, it is important to determine is the tubes are open. If they are, conventional treatment with ovulation induction and insemination can be tried for few cycles and if unsuccessful proceed to IVF. In cases where there is anatomical disease with scarring and damaged tubes or ovaries, IVF would be the most suitable treatment from the outset.
Click To View “Understanding Endometriosis” with Dr. Michele Evans
Previous SurgeriesAnother common cause of tubal disease is the result of pelvic or abdominal surgical procedures. Some of these procedures could have been performed for gynecological conditions such as ovarian cysts, endometriosis or fibroid tumors or non-gynecological conditions such as appendicitis or diverticulitis.
Any time a “cut” is made in an organ such as the ovary or the uterus, the body will react by producing scar tissue in the ensuing weeks. The same concept occurs on the skin. A deep cut usually result s in scarring. Unfortunately, if the scarring affects crucial structures such as the Fallopian tubes, the result could be the inability of the tube to move freely in order to pick the ovulated egg from the surface of the ovary. If the scarring affects the surface of the ovary on the other hand, a “blanket” is formed covering and preventing the egg from pick-up.
A history of pelvic or abdominal surgeries is a clear indication to test the integrity of the Fallopian tubes (see Testing). In some cases, laparoscopy is required as the only sure way of ruling out tubal scarring. In this procedure, a telescopic-like instrument is introduced through the umbilicus in an outpatient setting and the tubes evaluated.
GeneticIn rare instance, a woman is born with congenitally absent Fallopian tubes. Other anomalies usually accompany such findings such as abnormal uterus or even ovaries.
The diagnosis is usually reached following laparoscopic evaluation.
The treatment is In Vitro Fertilization.
Uterine DiseaseThe uterus is the incubator where the zygote implants and grows. Any abnormality affecting this organ can result in infertility or even a miscarriage.
The uterus is pear-shaped hollow organ about 3 inches long and 2 inches wide. During pregnancy it can grow enough to contain a 10 lbs baby! The body of the uterus is composed of “smooth” muscular tissue. The cavity is lined with a specialized layer of cells called the “Endometrium”. This layer is equivalent to the soil and is crucial in the implantation process. The Endometrium has to be devoid of any abnormalities and should reach a certain thickness to be able to sustain a pregnancy. Hormones produced by the ovaries, Estrogen and Progesterone, help prepare the Endometrium for implantation.
As part of the investigative process, every woman suffering from infertility should have her uterus evaluated prior to any treatment. This is accomplished by a pelvic ultrasound examination.
Certain conditions affecting the uterus can result in infertility as discussed in this section.
FibroidsFibroids or myomas are benign tumors of the muscle of the uterus. They are very common and almost 1 in 4 women will harbor fibroids once during their lifetime.
Fibroids generally are harmless. They can attain different sizes. They start as miniature cellular growths and can attain sizes of 10-20 inches in diameter. They grow under the influence of Estrogen hormone and can get large in pregnancy and even interfere with delivery. If large, they can present with symptoms such as discomfort, pain with intercourse, heaviness, urinary symptoms and abnormal bleedings. Fibroids shrink after menopause when the body’s Estrogen levels drop.
The location of fibroids is important in determining its harmfulness. They can be in the body of the uterus, called “Intramural” fibroids, on the outside of the uterus attached to it with a pedicle, called “Serosal or pedunculated” fibroids, or inside the uterine cavity or “Submucosal” fibroids. When fibroids are large and close to the lining of the uterus, they can interfere with implantation and cause infertility or miscarriages and have to be removed before attempting to conceive again. Therefore, the two instances where fibroids can be troublesome, are when they are “too large” or when they are impinging on the endometrium.
Click To View “Understanding Fibroids” with Dr. Catherine DeUgarte
AdhesionsAdhesions or scar tissue inside the uterine cavity can also interfere with fertility. The most common causes of adhesions include:
Previous surgical manipulation of the uterine cavity such as D&C, fibroid or polyp surgery or to remove retained placentas after a delivery.
A D&C or Dilatation and Curettage is the procedure whereby the cavity of the uterus is scraped to remove abnormal tissue. The damage usually occurs when the procedure is conducted aggressively or when it is done following the delivery of a baby or when it is complicated with an infection.
Many patients harboring such adhesions do not have any complaints or symptoms. It is diagnosed during the routine infertility investigation with a hysterosalpingogram or ultrasound examination. In some patients however, the scarring is so bad that there is absence of periods or very light period as most of the endometrium is covered with scarring. Since the endometrium is what is “shed” during the menstrual cycle, the less of it results in lighter periods.
Congenital AnomaliesSome women are born with congenital anomalies of the uterus. This can encompass a variety of abnormalities from mild to severe. In some cases, the uterus is totally absent or is extremely small. In others, the uterus is divided in two halves or a thick membrane is present in the middle of the cavity called “Septum”. Such abnormalities can interfere with the normal implantation of the zygote and result in infertility or miscarriages.
The diagnosis is usually made by the x-ray test called HSG or Hysterosalpingogram along with surgical exploration with laparoscopy.
The milder cases, such a small septum, can be easily fixed on an outpatient basis. In extreme anomalies, surrogacy is the only solution for a successful outcome.
UnexplainedA diagnosis of unexplained infertility is made when after a complete investigation, no obvious cause of infertility is found. It is a diagnosis of exclusion. Most of the time however, patients are labeled with this diagnosis without completing all the necessary testing.
The prognosis of conceiving is not necessarily better if the diagnosis of unexplained infertility is made. To the contrary, it could indicate an etiology that could be more difficult to treat.
Occasionally, a diagnosis is reached following treatment such as with In Vitro Fertilization. For instance, a subset of patients suffers from infertility because of poor fertilizing capability of sperm. When an IVF cycle is done in these patients, fertilization would be poor and therefore the diagnosis of male factor is reached.
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