Symptoms and Causes of Infertility

Symptoms

The main symptom of infertility is the inability to get pregnant. A menstrual cycle that's too long (35 days or more), too short (less than 21 days), irregular or absent can mean that the woman is not ovulating. There may be no other outward signs or symptoms.

When to see a doctor

When to seek help sometimes depends on your age:

• Up to age 35, most doctors recommend trying to get pregnant for at least a year before testing or treatment.
• If you're between 35 and 40, discuss your concerns with your doctor after six months of trying.
• If you're older than 40, your doctor may want to begin testing or treatment right away.

Your doctor may also want to begin testing or treatment right away if you or your partner has known fertility problems, or if you have a history of irregular or painful periods, pelvic inflammatory disease, repeated miscarriages, prior cancer treatment, or endometriosis.

Female reproductive system

Fertilization and implantation

Fertilization and implantation

Causes

Each of these factors is essential to become pregnant:

• You need to ovulate. To get pregnant, your ovaries must produce and release an egg, a process known as ovulation. Your doctor can help evaluate your menstrual cycles and confirm ovulation.
• Your partner needs sperm. For most couples, this isn't a problem unless your partner has a history of illness or surgery. Your doctor can run some simple tests to evaluate the health of your partner's sperm.
• You need to have regular intercourse. You need to have regular sexual intercourse during your fertile time. Your doctor can help you better understand when you're most fertile.
• You need to have open fallopian tubes and a normal uterus. The egg and sperm meet in the fallopian tubes, and the embryo needs a healthy uterus in which to grow.

For pregnancy to occur, every step of the human reproduction process has to happen correctly. The steps in this process are:

• One of the two ovaries releases a mature egg.
• The egg is picked up by the fallopian tube.
• Sperm swim up the cervix, through the uterus and into the fallopian tube to reach the egg for fertilization.
• The fertilized egg travels down the fallopian tube to the uterus.
• The fertilized egg implants and grows in the uterus.

In women, a number of factors can disrupt this process at any step. Female infertility is caused by one or more of the factors below:

Ovulation disorders

Ovulation disorders, meaning you ovulate infrequently or not at all, account for infertility in about 1 in 4 infertile couples. Problems with the regulation of reproductive hormones by the hypothalamus or the pituitary gland, or problems in the ovary, can cause ovulation disorders.

• Polycystic ovary syndrome (PCOS). PCOS causes a hormone imbalance, which affects ovulation. PCOS is associated with insulin resistance and obesity, abnormal hair growth on the face or body, and acne. It's the most common cause of female infertility.
• Hypothalamic dysfunction. Two hormones produced by the pituitary gland are responsible for stimulating ovulation each month — (FSH) and luteinizing hormone (LH). Excess physical or emotional stress, a very high or very low body weight, or a recent substantial weight gain or loss can disrupt production of these hormones and affect ovulation. Irregular or absent periods are the most common signs.
• Premature ovarian failure. Also called primary ovarian insufficiency, this disorder is usually caused by an autoimmune response or by premature loss of eggs from your ovary (possibly from genetics or chemotherapy). The ovary no longer produces eggs, and it lowers estrogen production in women under the age of 40.
• Too much prolactin. The pituitary gland may cause excess production of prolactin (hyperprolactinemia), which reduces estrogen production and may cause infertility. Usually related to a pituitary gland problem, this can also be caused by medications you're taking for another disease.

Damage to fallopian tubes (tubal infertility)

Damaged or blocked fallopian tubes keep sperm from getting to the egg or block the passage of the fertilized egg into the uterus. Causes of fallopian tube damage or blockage can include:

• Pelvic inflammatory disease, an infection of the uterus and fallopian tubes due to chlamydia, gonorrhea or other sexually transmitted infections
• Previous surgery in the abdomen or pelvis, including surgery for ectopic pregnancy, in which a fertilized egg implants and develops in a fallopian tube instead of the uterus
• Pelvic tuberculosis, a major cause of tubal infertility worldwide, although uncommon in the United States

Endometriosis

Endometriosis occurs when tissue that normally grows in the uterus implants and grows in other locations. This extra tissue growth — and the surgical removal of it — can cause scarring, which may block fallopian tubes and keep an egg and sperm from uniting.

Endometriosis can also affect the lining of the uterus, disrupting implantation of the fertilized egg. The condition also seems to affect fertility in less-direct ways, such as damage to the sperm or egg.

Uterine or cervical causes

Several uterine or cervical causes can impact fertility by interfering with implantation or increasing the likelihood of a miscarriage:

• Benign polyps or tumors (fibroids or myomas) are common in the uterus. Some can block fallopian tubes or interfere with implantation, affecting fertility. However, many women who have fibroids or polyps do become pregnant.
• Endometriosis scarring or inflammation within the uterus can disrupt implantation.
• Uterine abnormalities present from birth, such as an abnormally shaped uterus, can cause problems becoming or remaining pregnant.
• Cervical stenosis, a narrowing of the cervix, can be caused by an inherited malformation or damage to the cervix.
• Sometimes the cervix can't produce the best type of mucus to allow the sperm to travel through the cervix into the uterus.

Unexplained infertility

Sometimes, the cause of infertility is never found. A combination of several minor factors in both partners could cause unexplained fertility problems. Although it's frustrating to get no specific answer, this problem may correct itself with time. But, you shouldn't delay treatment for infertility.

Risk factors

Certain factors may put you at higher risk of infertility, including:

• Age. The quality and quantity of a woman's eggs begin to decline with increasing age. In the mid-30s, the rate of follicle loss speeds, resulting in fewer and poorer quality eggs. This makes conception more difficult, and increases the risk of miscarriage.
• Smoking. Besides damaging your cervix and fallopian tubes, smoking increases your risk of miscarriage and ectopic pregnancy. It's also thought to age your ovaries and deplete your eggs prematurely. Stop smoking before beginning fertility treatment.
• Weight. Being overweight or significantly underweight may affect normal ovulation. Getting to a healthy body mass index (BMI) may increase the frequency of ovulation and likelihood of pregnancy.
• Sexual history. Sexually transmitted infections such as chlamydia and gonorrhea can damage the fallopian tubes. Having unprotected intercourse with multiple partners increases your risk of a sexually transmitted infection that may cause fertility problems later.
• Alcohol. Stick to moderate alcohol consumption of no more than one alcoholic drink per day.

Diagnosis

By Mayo Clinic Staff

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Hysterosalpingography

If you've been unable to conceive within a reasonable period of time, seek help from your doctor for evaluation and treatment of infertility.

Fertility tests may include:

• Ovulation testing. An at-home, over-the-counter ovulation prediction kit detects the surge in luteinizing hormone (LH) that occurs before ovulation. A blood test for progesterone — a hormone produced after ovulation — can also document that you're ovulating. Other hormone levels, such as prolactin, also may be checked.
• Hysterosalpingography. During hysterosalpingography (his-tur-o-sal-ping-GOG-ruh-fee), X-ray contrast is injected into your uterus and an X-ray is taken to detect abnormalities in the uterine cavity. The test also determines whether the fluid passes out of the uterus and spills out of your fallopian tubes. If abnormalities are found, you'll likely need further evaluation. In a few women, the test itself can improve fertility, possibly by flushing out and opening the fallopian tubes.
• Ovarian reserve testing. This testing helps determine the quality and quantity of eggs available for ovulation. Women at risk of a depleted egg supply — including women older than 35 — may have this series of blood and imaging tests.
• Other hormone testing. Other hormone tests check levels of ovulatory hormones as well as thyroid and pituitary hormones that control reproductive processes.
• Imaging tests. A pelvic ultrasound looks for uterine or fallopian tube disease. Sometimes a hysterosonography (his-tur-o-suh-NOG-ruh-fee) is used to see details inside the uterus that can't be seen on a regular ultrasound.

Depending on your situation, rarely your testing may include:

• Other imaging tests. Depending on your symptoms, your doctor may request a hysteroscopy to look for uterine or fallopian tube disease.
• Laparoscopy. This minimally invasive surgery involves making a small incision beneath your navel and inserting a thin viewing device to examine your fallopian tubes, ovaries and uterus. A laparoscopy may identify endometriosis, scarring, blockages or irregularities of the fallopian tubes, and problems with the ovaries and uterus.
• Genetic testing. Genetic testing helps determine whether there's a genetic defect causing infertility.

Treatment

By Mayo Clinic Staff

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Infertility treatment depends on the cause, your age, how long you've been infertile and personal preferences. Because infertility is a complex disorder, treatment involves significant financial, physical, psychological and time commitments.

Although some women need just one or two therapies to restore fertility, it's possible that several different types of treatment may be needed.

Treatments can either attempt to restore fertility through medication or surgery, or help you get pregnant with sophisticated techniques.

Fertility restoration: Stimulating ovulation with fertility drugs

Fertility drugs regulate or stimulate ovulation. Fertility drugs are the main treatment for women who are infertile due to ovulation disorders.

Fertility drugs generally work like the natural hormones — follicle-stimulating hormone (FSH) and luteinizing hormone (LH) — to trigger ovulation. They're also used in women who ovulate to try to stimulate a better egg or an extra egg or eggs. Fertility drugs may include:

• Clomiphene citrate. Clomiphene (Clomid) is taken by mouth and stimulates ovulation by causing the pituitary gland to release more FSH and LH, which stimulate the growth of an ovarian follicle containing an egg.
• Gonadotropins. Instead of stimulating the pituitary gland to release more hormones, these injected treatments stimulate the ovary directly to produce multiple eggs. Gonadotropin medications include human menopausal gonadotropin or hMG (Menopur) and FSH (Gonal-F, Follistim AQ, Bravelle). Another gonadotropin, human chorionic gonadotropin (Ovidrel, Pregnyl), is used to mature the eggs and trigger their release at the time of ovulation. Concerns exist that there's a higher risk of conceiving multiples and having a premature delivery with gonadotropin use.
• Metformin. Metformin (Glucophage, others) is used when insulin resistance is a known or suspected cause of infertility, usually in women with a diagnosis of PCOS. Metformin helps improve insulin resistance, which can improve the likelihood of ovulation.
• Letrozole. Letrozole (Femara) belongs to a class of drugs known as aromatase inhibitors and works in a similar fashion to clomiphene. Letrozole may induce ovulation. However, the effect this medication has on early pregnancy isn't yet known, so it isn't used for ovulation induction as frequently as others.
• Bromocriptine. Bromocriptine (Cycloset), a dopamine agonist, may be used when ovulation problems are caused by excess production of prolactin (hyperprolactinemia) by the pituitary gland.

Risks of fertility drugs

Using fertility drugs carries some risks, such as:

• Pregnancy with multiples. Oral medications carry a fairly low risk of multiples (less than 10 percent) and mostly a risk of twins. Your chances increase up to 30 percent with injectable medications. Injectable fertility medications also carry the major risk of triplets or more (higher order multiple pregnancy).

Generally, the more fetuses you're carrying, the greater the risk of premature labor, low birth weight and later developmental problems. Sometimes adjusting medications can lower the risk of multiples, if too many follicles develop.

• Ovarian hyperstimulation syndrome (OHSS). Injecting fertility drugs to induce ovulation can cause OHSS, which causes swollen and painful ovaries. Signs and symptoms usually go away without treatment, and include mild abdominal pain, bloating, nausea, vomiting and diarrhea.

If you become pregnant, however, your symptoms might last several weeks. Rarely, it's possible to develop a more-severe form of OHSS that can also cause rapid weight gain, enlarged painful ovaries, fluid in the abdomen and shortness of breath.

• Long-term risks of ovarian tumors. Most studies of women using fertility drugs suggest that there are few if any long-term risks. However, a few studies suggest that women taking fertility drugs for 12 or more months without a successful pregnancy may be at increased risk of borderline ovarian tumors later in life.

Women who never have pregnancies have an increased risk of ovarian tumors, so it may be related to the underlying problem rather than the treatment. Since success rates are typically higher in the first few treatment cycles, re-evaluating medication use every few months and concentrating on the treatments that have the most success appear to be appropriate.

Fertility restoration: Surgery

Several surgical procedures can correct problems or otherwise improve female fertility. However, surgical treatments for fertility are rare these days due to the success of other treatments. They include:

• Laparoscopic or hysteroscopic surgery. These surgeries can remove or correct abnormalities to help improve your chances of getting pregnant. Surgery might involve correcting an abnormal uterine shape, removing endometrial polyps and some types of fibroids that misshape the uterine cavity, or removing pelvic or uterine adhesions.
• Tubal surgeries. If your fallopian tubes are blocked or filled with fluid (hydrosalpinx), your doctor may recommend laparoscopic surgery to remove adhesions, dilate a tube or create a new tubal opening. This surgery is rare, as pregnancy rates are usually better with IVF. For hydrosalpinx, removal of your tubes (salpingectomy) or blocking the tubes close to the uterus can improve your chances of pregnancy with IVF.

Reproductive assistance

The most commonly used methods of reproductive assistance include:

• Intrauterine insemination (IUI). During IUI, millions of healthy sperm are placed inside the uterus close to the time of ovulation.
• Assisted reproductive technology. This involves retrieving mature eggs from a woman, fertilizing them with a man's sperm in a dish in a lab, then transferring the embryos into the uterus after fertilization. IVF is the most effective assisted reproductive technology. An IVF cycle takes several weeks and requires frequent blood tests and daily hormone injections.

http://www.mayoclinic.org/diseases-conditions/female-infertility/diagnosis-treatment/treatment/txc-20231648 (3)

Causes of female infertility

Disorders of ovulation

They may occur at the level of pituitary or hypothalamus as well as at the level of the ovary. If there is amenorrhoea it should be investigated as such and oligomenorrhoea along similar lines.

The World Health Organization (WHO) classifies ovulation disorders into three groups:

• Group I: hypothalamic pituitary failure (hypothalamic amenorrhoea or hypogonadotrophic hypogonadism).
• Group II: hypothalamic-pituitary-ovarian dysfunction, predominately a result of polycystic ovary syndrome (PCOS). This is the cause of the vast majority of ovulation disorder.
• Group III: ovarian failure.

As above, PCOS is responsible for the majority of ovulation disorders. Others include:

• Pituitary tumours can displace or destroy normal tissue and the production of follicle-stimulating hormone (FSH) and luteinising hormone (LH) is often the first to be affected. Panhypopituitarism is also called Simmonds' disease.
• Sheehan's disease is pituitary infarction following postpartum haemorrhagic shock.
• Hyperprolactinaemia may present with galactorrhoea or amenorrhoea. The control of prolactin (PRL) is unlike the other releasing factors, in that it is controlled by an inhibiting rather than a releasing factor from the hypothalamus into the hypothalamic-pituitary portal circulation. It is also released in response to thyrotropin-releasing factor, as is thyroid-stimulating hormone (TSH), and so it is elevated if thyroxine is low.
• The pituitary gland may be responsible for other disorders such as Cushing's syndrome.
• A number of chromosomal disorders result in inadequate ovarian function and usually primary amenorrhoea:
• Turner syndrome - there is a loss or abnormality of the second X chromosome in at least one cell line in a phenotypic female. The ovaries are usually just streaks. This condition may be a mosaic.
• In testicular feminisation there is primary amenorrhoea. The karyotype is XY but there is androgen insensitivity.
• XXY, or Klinefelter's syndrome, appears as a male.
• The XXX karyotype - this is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births. While fertility in women with trisomy X is generally considered normal, there is an increased risk for premature ovarian failure.
• Premature ovarian failure or premature menopause (menopause that occurs <40 years, although many gynaecologists use <45 years) causes secondary amenorrhoea. Premature ovarian failure occurs in about 1% of women.

Problems of tubes, uterus or cervix

• The Fallopian tubes are delicate structures whose cilia waft the ovum, or even early embryo, to its destination for implantation - more correctly called nidation:
• Damage to the tubes may occur as a result of infection:
• A history of pelvic inflammatory disease (PID) is highly suggestive of damage to tubes.
• Severe pelvic infection following illegal abortion is rarely seen in this country but still occurs in places where termination of pregnancy is illegal or difficult to secure.
• Even a legal termination or miscarriage can lead to infection of retained products of conception.
• Postpartum infection can also affect fertility.
• Sexually transmitted infections may cause infertility, largely through associated PID. Chlamydia and gonorrhoea are the most important.
• Infection may be less direct, and spread from appendicitis is possible, even without overt peritonitis.
• Female sterilisation operations involve disruption of the tube and results of attempted reversal are poor. Laparoscopic proof of patency of the tubes is not necessarily evidence that they function normally.
• Infection can also damage the uterus. Adhesions in the uterus and cervix are called Asherman's syndrome.[2]
• Deformity of the uterus, such as a septum or bicornuate uterus, may be more likely to cause recurrent abortion than failure to conceive.
• Significant distortion of the uterine cavity by fibroids can prevent implantation and hence fertility, although the impact on fertility remains a subject for debate.
• The cervix may have been shortened and damaged by a cone biopsy.
• There may be problems of cervical mucus, including hostility to sperm.
• Endometriosis may cause such inflammation, adhesion and distortion in the pelvis that it causes tubal infertility. Even when it is much less severe than that, it is commonly associated with subfertility.[3]There is evidence for improvement in conception rates following surgery but not medical treatment of endometriosis.[4]

History[1]

General health

Even in the absence of systemic illness, poor general health will impair fertility. Enquire about general lifestyle, including smoking, alcohol and recreational drug use, in addition to exercise and dietary intake.

• Aim for an ideal BMI:
• Women with a BMI of <19 and who have irregular menstruation or are not menstruating should be advised that increasing body weight is likely to improve their fertility.
• Women with a BMI of ≥30 should be informed that they are likely to take longer to conceive and those who are not ovulating should be informed that losing weight is likely to increase their chance of conception.
• Participating in a group programme involving exercise and dietary advice, rather than receiving weight loss advice alone, leads to more pregnancies.
• Smoking cigarettes impairs fertility and smoking in pregnancy increases the risk of miscarriage, obstetric complications, intrauterine growth restriction and even delayed reading ability (at least to the age of 7).[5]
• Women who are trying to become pregnant should be informed that drinking no more than one or two units of alcohol once or twice per week and avoiding episodes of intoxication reduce the risk of harming a developing fetus. Excessive alcohol consumption impairs sperm quality in men and may affect fertility in women.[6, 7]
• There is currently insufficient evidence for a strong association between excessive caffeine consumption and poor pregnancy outcomes, including infertility.[8]
• Illicit drugs should be avoided. Some have adverse effects on fertility or the fetus or both and, for most, the question of teratogenicity has not been adequately addressed. Cannabis can impair ovulation and cocaine can cause tubal infertility. There is also reason to be concerned about the effect these drugs may have in pregnancy.

Sexual history

• Enquire about frequency of coitus (ideally two to three times a week) and any prolonged or recurrent absences of one of the partners.
• Ask about potential physical problems such as inadequate penetration or dyspareunia.

Past medical history

Previous treatment for malignancy (chemotherapeutic agents, such as those used in childhood leukaemia) may result in subsequent sterility. Surgery and radiotherapy may be relevant if they involved the pelvic region.

Systemic disease may impair fertility, probably by interference with the hypothalamic-pituitary axis:

• This may include autoimmune disease such as rheumatoid disease or systemic lupus erythematosus (SLE), although the latter - eg, antiphospholipid syndrome - may be associated with recurrent miscarriage.[9]
• Chronic kidney disease can impair fertility.
• Poorly controlled diabetes mellitus should be improved.
• Anorexia nervosa can cause anovulation and amenorrhoea.

Medication and drug history

A thorough review of all medication is required with a view to both fertility and possible adverse effects on pregnancy, including teratogenicity. A number of recreational drugs may have an adverse effect on fertility, as above. Some prescribed medication may also cause problems:

• Phenothiazines and the older typical antipsychotics as well as metoclopramide can increase levels of PRL.
• Non-steroidal anti-inflammatory drug (NSAID) use is associated with luteinised unruptured follicles.[10]
• Immunosuppressants, used in autoimmune disease or post-transplant, may also affect fertility.

Examination

• Look for signs of hirsutism:
• Facial hair may be more profuse than normal, although this should be interpreted in the light of racial norms.
• Acne may also indicate high androgen levels.
• There may be a hint of male pattern alopecia with slight bitemporal recession.
• The pubic hairline may extend up towards the umbilicus in a typical male pattern.
• Abdominal examination should be performed and it must precede bimanual pelvic examination or it is very easy to miss a large mass such as a big ovarian cyst.
• Gynaecological examination, especially vaginal examination, may indicate undisclosed sexual difficulties - eg, vaginismus.
• Bimanual examination: may detect an adnexal mass from an ovary of tubo-ovarian mass or tenderness suggesting PID or endometriosis, or the presence of uterine fibroids.

Investigations[1]

The search for the cause of infertility or subfertility should be systematic and led by clinical features, not a blind screening process for everything.

• Mid-luteal progesterone level to assess ovulation:
• If low, it may need repeating, as ovulation does not occur every month.
• The blood test is taken seven days before the anticipated period, ie on day 21 of a 28-day cycle. However, this day will need to be adjusted for different lengths of cycle
• FSH and LH should be measured if there is menstrual irregularity:
• High levels may suggest poor ovarian function.
• A comparatively high LH level relative to FSH level can occur in PCOS.
• Women who are concerned about their fertility should be offered testing for their rubella status. Those women who are susceptible to rubella should be offered vaccination and advised not to become pregnant for at least one month following vaccination.
• Basal body temperature charts are not recommended to predict ovulation, as they are unreliable.
• Other tests are not recommended in primary care.

Secondary care investigations[1]

Each clinic may well have its own protocol for the investigation of couples in whom no problem has been identified, and even after extensive investigation no problem is found in 25%.

An earlier referral for specialist consultation should be offered when:

• The women is aged ≥36 years.
• There is a known cause of infertility.
• There is a history of predisposing factors for infertility.
• Investigations show there is apparently no chance of pregnancy with expectant management.

Tubal patency

Tubal damage is estimated to account for 20% of infertility in women.

• A hysterosalpingogram (HSG) or a hysterosalpingo-contrast ultrasound is recommended by the National Institute for Health and Care Excellence (NICE) for women who are not known to have comorbidities (such as PID, ectopic pregnancy or endometriosis).
• A laparoscopy and dye test is recommended for those women who are thought to have comorbidities
• Prior to undergoing uterine instrumentation, women should be offered screening for Chlamydia trachomatis and be treated appropriately if the result is positive.
• Prophylactic antibiotics should be considered before uterine instrumentation if screening has not been undertaken.

Ovarian reserve testing

The woman's age should be used as an initial predictor of her overall chance of success through natural conception.

One of the following measures should be used (measured around Day 3 of the menstrual cycle) to predict the likely ovarian response  to gonadotrophin stimulation in IVF:

• Total antral follicle count of ≤4 for a low response and >16 for a high response.
• Anti-Müllerian hormone of ≤5.4 pmol/L for a low response and ≥25.0 pmol/L for a high response.
• FSH >8.9 IU/L for a low response and <4 IU/L for a high response.

A high response results in more mature follicles developing, leading to higher-than-average pregnancy rates.

The following tests should not be used individually to predict any outcome of fertility treatment:

• Ovarian volume
• Ovarian blood flow
• Inhibin B
• Estradiol (E2)

People undergoing IVF treatment should be offered testing for HIV, hepatitis B and hepatitis C. Those people found to test positive for one or more of HIV, hepatitis B or hepatitis C should be offered specialist advice and counselling and appropriate clinical management.