IVF and Female Infertility: Causes, Diagnosis, and Treatment
In the previous chapter, we gave you a brief overview of what IVF is . To get a deeper understanding of what IVF is capable of treating, we need to learn about how the female reproductive system works. 1/3 of patients seeking IVF suffer from female factor infertility. For this reason, it’s important that women become aware of their reproductive health early on, and learn as much as they can about their bodies. In this chapter, we will learn about;
- The female reproductive system
- The menstrual cycle
- What causes infertility in women
- How IVF treats infertility in women
What is the female reproductive system and how does it work?
Vagina: Also known as the birth canal, the vagina is the canal that connects the internal sex organs with the external sex organs.
Cervix: Cervix is the lower part of the uterus. It separates the vagina and the ‘corpus’ (body) of the uterus, where the baby develops. During a natural birth, this canal will expand the allow the passage of the baby. During menstruation, it contracts and expands to allow the passage of the uterine lining.
Uterus: The uterus is the home of the embryo. This organ that is the size of a lemon can grow big enough to house a baby. During the menstrual cycle, the uterus prepares itself for pregnancy by making its inner structure strong to hold an embryo. If fertilization occurs, the embryo holds onto this structure to survive. When fertilization doesn’t occur, it rids itself of this membrane since there is no use for it.
Fallopian Tubes: Fallopian tubes connect the uterus to the ovaries. After ovulation, the egg travels through this tube. Fertilization usually happens in the fallopian tubes. After fertilization, the zygote travels down to the uterus and implants itself.
Ovaries: Ovaries are located on either side of the uterus, and are connected to it by the fallopian tubes. A woman’s lifetime supply of eggs is stored in the ovaries. A female child is born with one or two million egg cells. As the child grows and reaches adolescence, the number of eggs drops to around 300.000. In a lifetime a female will ovulate around 500 of these egg cells, which makes a woman fertile for around 37-39 years. With menopause, the unused egg cells decrease. Ovaries produce different hormones during different stages of the menstrual cycle.
What is menstruation and how does it work?
The purpose of the menstrual cycle is to prepare the body for pregnancy. It has 3 main phases that are characterized by the changing levels of specific hormones. The hormones are secreted by the ovaries, and the part of the brain called the pituitary gland dictates which hormones need to be produced at what time.
Follicular Phase: The first day of your period is the first day of your menstrual cycle. Your period is the first part of the follicular phase. When you’re on your period, this is your body’s way of getting rid of the uterine lining when you don’t get pregnant. A normal period lasts about 5 to 6 days.
In the follicular phase, a hormone called FSH (Follicle Stimulating Hormone) is produced by the pituitary gland. The purpose of FSH is to encourage the growth of follicles that reside in the ovaries. Each follicle houses an immature egg cell. With the help of FSH, these follicles start to grow. In each cycle, only 1 follicle becomes dominant and continues to develop. As it develops, the amount of FSH in the body decreases.
This dominant follicle starts producing Estrogen, commonly known as the female hormone. Estrogen makes the newly shed lining of the uterine thicker and changes the mucus to accommodate sperm cells in preparation for ovulation.
Ovulatory phase: As the follicle grows, and the estrogen levels increase, the pituitary gland that previously secreted FSH, starts secreting LH (Luteinizing Hormone). Its purpose is to mature the egg and trigger ovulation. During ovulation, the egg is released from the follicle and travels down the fallopian tube. This egg can only survive for 24 hours. If the egg doesn’t get fertilized, it dies. The follicle the egg grew in is left behind in the ovary, and the remains of it (corpus luteum) will be secreting progesterone in the luteal phase.
The ovulatory phase is also known as your ‘fertile window’. So if you want to get pregnant, this is the ideal time to try. As the released egg travels down the fallopian tube, it’s fertilized by sperm. In a few days, it will travel down to the womb and implant in the thickened uterine lining.
Luteal Phase: Luteal phase is between ovulation and the first day of the menstrual cycle. The follicle left behind in the ovaries starts to produce progesterone and estrogen. Progesterone will prevent the uterine lining from becoming too thick and makes it more habitable for a potential embryo. If you don’t get pregnant, you will shed this lining on your next period and the corpus luteum will disintegrate and the estrogen and progesterone levels will decrease, triggering menstruation.
If you do get pregnant, the embryo will implant itself, and start growing. The progesterone secreted by the corpus luteum will support the early pregnancy.
Why is it important to have regular periods?
Having regular periods is a sign of good health. Your period doesn’t need to fit into the 28-day standard, it can vary for a few days; your bleeding might be a day or two shorter, longer, or delayed. What is important is that it’s regular. Irregularity in menstruation can be caused by a myriad of health problems. For this reason, it’s important to consult a doctor if you’re having irregular periods as it could be a sign of infertility.
What causes female infertility?
Multiple different factors can cause infertility in women. These can range from general lifestyle factors to bigger and more complex health problems with genetic roots. Now we will take a look at what kind of problems can be present in your body and reproductive system and cause infertility. We will also inform you on what kind of tests and procedures are conducted to diagnose these issues.
As we learned above, ovulation is the release of the egg. If you have ovulation problems, the release of the egg can be too late or too early, or it might not happen at all. Naturally, if there is no egg present at the time sperm travels through the female reproductive tract, fertilization, therefore pregnancy cannot occur. And if the release time is skewed, you cannot be aware of your fertile period and might miss it. These are the most common symptoms of having ovulatory problems;
- Amenorrhea: We can describe this as not having your period.
- Anovulation: This is the absence of ovulation, so your body doesn’t release an egg.
- Oligomenorrhea: This is when you have more than 35 days in between the first days of your period, and means that you ovulate later than average.
- Polymenorrhea: This is when you have less than 21 days in between the first days of your period, and means you ovulate earlier than average.
What causes ovulation problems?
Your menstrual cycle can be disrupted for various reasons. Ovulation problems are usually caused by some sort of hormonal imbalance. Most of them have the symptoms mentioned above, so it might be difficult to predict what your specific diagnosis could be. If you have the symptoms mentioned above, you should contact a gynecologist to figure out what your diagnosis is as it can indicate you are at risk of infertility:
- Hyperprolactinemia: This is when you have an unusually high amount of prolactin in your body. Prolactin is the hormone that makes breast milk. So when the levels are too high, your body thinks you’ve recently given birth and are breastfeeding and prevents you from releasing an egg so you don’t become ‘pregnant’ again in a short period.
- Luteal phase defect: This is when your body doesn’t make enough progesterone to properly thicken the uterine lining, or the uterine lining doesn’t respond to the progesterone. When the lining of the uterus is not thick enough, and the embryo cannot implant itself properly this can result in miscarriages or frequent periods.
- PCOS: Polycystic Ovarian Syndrome is a hormonal ovulation disorder. The follicles in the ovary cannot develop properly due to high levels of male hormones in the body. Since they’re not developed enough, there is no ovulation and the follicles become cysts. PCOS is also linked with insulin resistance.
- Thyroid issues: Problems with the thyroid can cause anovulation, and luteal phase problems; resulting in skewed menstrual cycles and implantation problems like early miscarriage. 
- Diminished ovarian reserve: Ovarian reserves start to diminish around the age of 30 as the amount of estrogen produced by the body starts to decrease. As a woman reaches menopause, ovarian reserves keep decreasing, resulting in shorter and shorter menstrual cycles.
- Hormonal imbalances: Imbalances in hormone levels such as prolactin, or unusually high amounts of androgens can prevent ovulation.
- Tumors & cysts: Tumors in the reproductive system, thyroid, and brain can interfere with the proper function of these organs and the hormones secreted by them.
- Eating disorders: Due to severe malnutrition, the hypothalamus stops producing hormones that trigger ovulation since reproduction is not considered ‘essential’ for the body to stay alive.
- Alcohol & drug use: Alcohol and drugs can suppress your natural cycle and prevent ovulation [ 2]. Also, oxidative stress from alcohol and drug abuse can cause infertility by reducing oocyte quality.
- Obesity: As obesity alters the way the body works, it can cause ovulation problems. [ 3]
- Stress: Stress can alter the hormone levels in the body, causing anovulation. [ 4]
- Extreme exercise: Extreme exercise (more than 60 minutes a day) is associated with anovulation [ 5].
For your diagnosis, your doctor will conduct some hormonal tests;
- Hormone profile: Comprehensive tests are conducted to evaluate hormones that can affect ovulation including thyroids, prolactin, estrogen, etc.
- LH test: Levels of LH in your blood can determine if you’re ovulating or not.
- 21st-day serum progesterone levels: As stated at the beginning of this chapter, after ovulation occurs, the follicle the egg was separated from starts to secrete progesterone, and the amount of progesterone in the body peaks around day 21 of the cycle, and its levels can tell your doctor if you ovulate.
In addition to these tests, your doctor will check your ovarian reserves to see how many eggs you have, which directly indicates how fertile you are;
- Antral follicle count: The ovaries are examined with a transvaginal ultrasound for the presence and the number of follicles as those can give an idea if you’re ovulating or not [ 6].
- FSH & Estradiol: As we learned, FSH and estradiol are important parts of the ovulatory phase, and their levels can not only give your doctor an idea about your ovarian reserves but also how your body might react to ovarian hyperstimulation if you’re considering IVF.
- Anti-Mullerian Hormone test: AMH is produced by the follicles in the ovaries. AMH levels will give information on how many follicles you have left, and the quality of your eggs.
Why is the ovarian reserve so important?
Your ovarian reserves are directly correlated with how fertile you are. As we learned, a female child is born with a lifetime supply of eggs, and this number can only decrease. Having a low, or diminished ovarian reserve indicates infertility. Not only that, it’ll affect the protocol you’ll be following for infertility treatment.
Who should get tested for ovarian reserves?
Most women about to go through IVF will go through these tests, but if you;
- Are over the age of 35,
- have a history of early menopause in your family,
- previously had ovarian surgery,
- had chemotherapy or pelvic radiotherapy,
- have unexplained infertility,
- are a poor responder to ovarian hyperstimulation,
- are considering IVF, you should be tested for ovarian reserve.
Tubal & Endometrial Problems
Problems with the oviduct and the uterus can also indicate infertility. Having abnormal structures and damage to these organs can affect fertility, even if you have healthy ovaries; as they directly affect where fertilization occurs, and implantation. The most common problems that affect the uterus and the fallopian tubes are as follows;
- Pelvic surgery: If you had previous pelvic surgery, there might be some damage done to your reproductive organs.
- Pelvic Inflammatory Disease: Untreated STIs can breach the cervix and affect the upper reproductive system, damaging them in the process.
- Previous infections: Infections like tuberculosis can spread to the reproductive system if left untreated, causing infertility.
- Sterilization: If you got tubal ligation or bilateral salpingectomy surgery previously, you are sterile and cannot get pregnant naturally.
- Adhesions (Synechia): Adhesions due to previous infections and surgery can create blockages in the organs, such as tubal occlusion, preventing the semen from reaching the egg.
- Previous ectopic pregnancy: Previous ectopic pregnancy lowers the chance of normal implantation, and if surgical intervention is required, it can cause damage.
- Fibroids: Myoma Uteri or uterine fibroids can alter the shape of the uterus and create blockages that prevent the sperm from traveling properly.
- Polyps: Polyps can prevent the sperm from reaching the egg, and also prevents the embryo from implantation.
- Congenital malformations: Abnormalities in the shape of the womb, such as a uterine septum, a double uterus (Uterus Didelphys), or a partially developed uterus (Unicornuate Uterus) can make it difficult to get pregnant.
Some of these problems can be diagnosed during routine exams, or before IVF treatment. Some of the tests conducted for the diagnosis of these problems are;
- Ultrasonography: Abdominal and transvaginal ultrasounds are used to examine the reproductive organs.
- Hysterosalpingography: A contrasting liquid is injected into the uterus, and with a special x-ray machine, the formation of the womb and the fallopian tubes are examined. Hysterosalpingography can also have a positive effect on fertility even though it’s a diagnostic procedure.
- Saline Infusion Sonohysterography: This test uses soundwaves and a saline solution to check your uterus for abnormalities.
- Pelvic MRI: MRI is performed to look at the structure of the reproductive system for anomalies.
- Hysteroscopy: A small catheter is inserted from the vagina, passing the cervical canal, and into the uterus for examination.
- Laparoscopy: Laparoscopy is a minimally invasive operation where 4-6 small cuts are made into the abdomen, and a camera and tools are inserted from these cuts for operation. For women, laparoscopy can be used as both a diagnostic procedure and a treatment.
- Chromotubation: This is an additional procedure that can be performed during a laparoscopy. A dyed liquid is injected into the fallopian tubes to see if there is any blockage.
You can think of the cervix as the barrier between the vagina and the upper reproductive system, and the cervical canal is what connects them. When there is something wrong with the cervix, it can affect both the vagina and the rest of the system. For this reason, it’s important the cervix functions healthily without any blockages. Some of the common cervical problems are;
- Cervical mucus problems: When cervical mucus is healthy, it creates a suitable environment for the sperm. When this mucus becomes too thick, acidic, or has anti-sperm antibodies, it becomes hostile to sperm.
- Cervical deficiency: When the woman has cervical deficiency, the cervix dilates too soon, causing early birth and miscarriage.
- Polyps: Depending on their placement, polyps can block the cervical canal, or prevent the cervix from producing healthy mucus.
- Congenital defects & abnormalities: Conditions like Cervical Agenesis (absence of the cervix), Cervical Duplication (two cervices), and Cervical Hypoplasia (smaller cervix) can have severe effects on fertility.
The most common of these problems concerns cervical mucus. There is a test to analyze the cervical mucus;
- Post Coital Test (PCT): This test is performed approximately 2 hours after intercourse, and it checks if the sperm can survive in the mucus secreted by the cervix, and the reproductive system.
Endometriosis is one of the most common reproductive disorders. When you have endometriosis, tissue similar to the uterine lining starts to grow outside the uterus and starts spreading. The growth is usually limited to the rest of the reproductive system, but if it’s left untreated, this tissue can even reach up to the lungs. Sometimes, endometriosis can present with severe abdominal pain or no pain at all. It’s difficult to diagnose this condition without surgery, so most women never know, or never get a confirmation if they have endometriosis. Treatment options can range from the use of birth control to invasive surgery. Some tests that can diagnose endometriosis are;
- Transvaginal ultrasonography: Using ultrasound is the least invasive method to see if you have endometriosis or not. While ultrasound can show the presence of tissue growth outside the uterus, confirmation is needed with laparoscopy.
- Laparoscopy: Laparoscopy is THE procedure when it comes to the diagnosis and treatment of endometriosis. For diagnosis, it’s used to get a biopsy sample. When it’s done for treatment, the laparoscopic method is used to remove the growth from abdominal organs.
- Hysterosalpingography: When you have endometriosis, HSG is used to see if the endometrial growth caused blockages in your reproductive system.
Drug use & Treatments
Some drugs and medications can interfere with the functions of the reproductive system. Some of them can cause direct harm to the organs through various mechanisms like oxidative stress. Some of them interact with the hormones that rule the menstrual cycle, thus affecting the way it works properly. Some damage caused by drugs is permanent and some are temporary. People must avoid illegal drugs first and foremost, and they should be informed about how prescription and over-the-counter medications can also interfere with their fertility.
- Substance abuse: Use of illegal or harmful drugs can damage the reproductive system.
- Cancer Treatment: Chemotherapy can interfere with ovarian functions and cause Primary Ovarian Insufficiency (POI). For this reason, It’s important that women going through cancer treatments consider a form of fertility preservation beforehand. Pelvic radiotherapy can also damage the ovarian reserve.
- Non-steroid anti-inflammatory drugs: Consistent use of NSAIDs can interfere with the menstrual cycle, implantation, and formation of the placenta.
- Psychiatric Medications: Antipsychotic medications used in the treatment of disorders like Bipolar and Schizophrenia can increase the levels of prolactin in the body and prevent ovulation.
- Spironolactone: Spironolactone use can stop menstruation, however, it doesn’t cause permanent infertility, and many women can become pregnant after stopping its use.
Age is one of the most important factors- if not the most important factor affecting fertility. Women are fertile only for a certain amount of time. Between adolescence and menopause, a woman will ovulate around 500 times. After the age of 35, it’s difficult to get pregnant as the ovarian reserves start to decrease. Not only that, but the quality of the eggs also decreases significantly with age. It becomes harder to get pregnant naturally. And because of this reduction in quality, getting pregnant over 35 comes with risks; both for the mother and the child. For older women, miscarriage and genetic abnormalities are more common.
As we will see in later chapters, age determines IVF success. For this reason, it’s important to take charge of your fertility at a young age, and consider some form of fertility preservation.
Genetic diseases can affect specific systems in the body or multiple ones. Some genetic disorders directly affect fertility because it’s affecting sex chromosomes, hormones, and organs; while in other cases these problems can be secondary symptoms. As technology and medicine have evolved, we are able to screen for abnormalities during IVF and pregnancy. With some genetic diseases, people can live long and happy lives but might face fertility issues. Some genetic diseases that affect the reproductive system are:
Kallmann syndrome: KS is a genetic disease where there is no onset of puberty and no development of secondary sex characteristics. Since the body doesn’t produce sex hormones, the necessary mechanisms for reproduction don’t reach maturity.
Fragile X syndrome: Women with Fragile-X syndrome and women who are carriers of its gene mutation can develop Fragile X-associated primary ovarian insufficiency (FXPOI), which is early menopause.
Primary ciliary dyskinesia: In females, PCD affects the fallopian tubes, and makes them unsuitable for sperm movement.
Galactosemia: This metabolical disorder is characterized by the body’s inability to metabolize sugars. If not detected in infancy, it can lead to death. However, with early diagnosis, people can avoid symptoms by removing dairy from their diet. Most women who have this condition develop primary ovarian insufficiency.
Prader-Willi syndrome: PWS is caused by the lack of HGH secretion. Naturally, reproductive organs cannot develop properly and the person doesn’t go through puberty and reach sexual maturation.
Pseudohypoparathyroidism type 1a: Due to a genetic mutation, the thyroid cannot control electrolytes, vitamins, and hormones. Since the thyroid is not responsive to sex hormones.
BPES Type I: BPES is characterized by small, narrow, and droopy eyes that have an upwards fold. BPES Type 1 also affects the ovaries, causing premature ovarian insufficiency.
Demirhan syndrome: Primarily affecting the skeletal system. It is also characterized by an underdeveloped reproductive system, insufficient ovarian reserve, and hormone production. 
Ataxia-telangiectasia syndrome: Also known as Louis-Bar syndrome, this genetic disease causes delayed or incomplete puberty and early menopause.
The immune system is your body’s defense mechanism. Its purpose is to protect you from organisms that can cause harm, and fight them. However, the immune system is delicate, and sometimes it can get confused. Auto-immune disorders occur when the immune system cannot differentiate what is something that’s trying to harm you and what’s a part of your body, so it starts attacking the body’s own systems.
An undiagnosed auto-immune disease can cause diminished ovarian reserves in women. Thyroid problems can also present problems since the thyroid interacts with the sex hormones. Additionally, the autoimmune disorders themselves, and the medications used in their treatment and management can cause problems. For this reason, women that have an auto-immune disease should be treated before considering IVF.
If you’re having recurrent miscarriages, you should be screened for Antiphospholipid Antibody Syndrome. With this disorder, the body starts to attack the placental tissue developed for the baby, causing miscarriage in addition to problems with clotting.
- If you have primary infertility because of ovulation problems, IVF can help you. An important aspect of IVF is ovulation induction. If you cannot release an egg on your own, you’ll be prescribed fertility drugs that will help you. This form of hormonal therapy is essential to the IVF process, and even if your cycle fails, it can have a positive effect on your overall reproductive health.
- You still have a chance of pregnancy with IVF after tubal ligation, or if you have damaged tubes. IVF completely avoids the fallopian tubes. As long as you can produce enough follicles and the embryo can implant, there is a chance that you can get pregnant.
- If you’re having problems with implantation and experiencing recurrent pregnancy loss, you’ll be given medications that will help your uterine lining become more suitable for implantation. In addition to that, there are multiple procedures to optimize endometrial receptivity.
- If you have any blockages in your reproductive system that are caused by fibroids or polyps you weren’t aware of, they’ll be diagnosed during the IVF process and be treated.
- If you take steps early on in life, IVF can help you with preserving your fertility before your ovarian reserves start to diminish.
- If you suffer from genetic diseases, IVF can help you avoid passing down these diseases to your children with the use of genetic screening.
- If you’re having problems with secondary infertility IVF can help you get pregnant once more.
- If you do not have a clear diagnosis, IVF has the highest succes rates for unexplianed infertility.