REPRODUCTIVE ENDOCRINOLOGY

Infertility

Infertility may be due to a single cause in either you or your partner, or a combination of factors that may prevent a pregnancy from occurring or continuing. Fortunately, there are many safe and effective therapies for overcoming infertility. These treatments significantly help in becoming pregnant.

Symptoms

Most couples achieve pregnancy within the first six months of unprotected intercourse. Overall, after 12 months of frequent unprotected intercourse, about 90 percent of couples will become pregnant. The majority of couples will eventually conceive, with or without treatment.

The main sign of infertility is the inability for a couple to get pregnant. There may be no other obvious symptoms.

In some cases, an infertile woman may have irregular or absent menstrual periods. An infertile man may have signs of hormonal problems, such as changes in hair growth, sexual function, reduced sexual desire, or problems with ejaculation.  He may also have small testicles or a swelling in the scrotum.

When to see a doctor

In general, you may consider seeing a doctor about infertility if you and your partner has been trying regularly to conceive for at least one year. You may consider being seen earlier if you are a woman and:

·        Your age ranges from 35 to 40 and have been trying to conceive for six months or longer

·        Your age is above 40

·        You menstruate irregularly or not at all

·        You have known fertility problems

·        You have been diagnosed with endometriosis or pelvic inflammatory disease

·        You have had more than one miscarriage

·        You have had prior cancer treatment

If you are a man, and you may wish to be evaluated sooner if you have:

·        A low sperm count or other problems with sperm

·        Swelling in the scrotum.

·        You have had a previous vasectomy

·        Undergone prior scrotal or inguinal surgery

·        Small testicles or problems with sexual function or desire

·        Had prior cancer treatment

·        Desire to know your fertility status

Causes

To become pregnant, the complex processes of ovulation and fertilization need to work properly. For some couples, infertility problems can be present from birth (congenital) or something can go wrong along the way that results in infertility.

The reasons for infertility can involve one or both partners. In general:

·        In about one-third of cases, the cause of infertility involves only the male.

·        In about one-third of cases, the cause of infertility involves only the female.

·        In the remaining cases, the cause of infertility involves both the male and female, or no cause can be identified.

Causes of male infertility

Causes of male infertility may include the following:

·        Abnormal sperm production or function: Due to various problems, like, undescended testicles, genetic defects, health problems including diabetes, prior infections such as mumps, trauma or prior surgeries on the testicles or inguinal region. Enlarged veins in the testes can increase blood flow and heat, affecting the number and shape of sperm.

·        Problems with the delivery of sperm: Due to sexual problems, such as premature ejaculation, semen entering the bladder instead of emerging through the penis during orgasm (retrograde ejaculation), certain genetic diseases like, cystic fibrosis, structural problems, such as blockage of the part of the testicle that contains sperm (epididymis), or damage or injury to the reproductive organs. Men who have previously undergone a vasectomy and desire a return of fertility will also need to either have the vasectomy reversed or have sperm retrieved through a surgical procedure for use in assisted reproductive techniques.

Fig 1: Causes of male infertility

·        Overexposure to certain chemicals and toxins: Chemicals and toxins such as, pesticides, radiation, tobacco smoke, alcohol, marijuana, and steroids (including testosterone also, frequent exposure to heat, such as in saunas or hot tubs, can elevate the testicular temperature, impairing sperm production.

·        Damage related to cancer and its treatment: This includes radiation or chemotherapy. Treatment for cancer can impair sperm production, sometimes severely. Removal of one testicle due to cancer also may affect male fertility.

Causes of female infertility

Causes of female infertility may include:

·        Ovulation disorders: These hinder or prevent the ovaries from releasing eggs. For example, hormonal disorders such as polycystic ovary syndrome, a condition that might relate to your ovaries producing too much of the male hormone testosterone, and hyperprolactinemia, i.e. when you have too much prolactin — the hormone that stimulates breast milk production. Other underlying causes may include excessive exercise, eating disorders, injury or tumors.

·        Uterine or cervical abnormalities: These include problems with the opening of the cervix or cervical mucus, or abnormalities in the shape or cavity of the uterus. Benign tumors in the wall of the uterus that are common in women (uterine fibroids) may rarely cause infertility by blocking the fallopian tubes. More often, fibroids may distort the uterine cavity interfering with implantation of the fertilized egg.

·        Fallopian tube damage or blockage: This usually results from inflammation of the fallopian tube (salpingitis). This can result from pelvic inflammatory disease, usually caused by sexually transmitted infection, endometriosis or adhesions.

·        Endometriosis: This occurs when endometrial tissue implants and grows outside of the uterus — often affecting the function of the ovaries, uterus and fallopian tubes.

·        Primary ovarian insufficiency: This is also called early menopause, when the ovaries stop working and menstruation ends before age 40. Although the cause is often unknown, certain conditions are associated with early menopause, including immune system diseases, radiation or chemotherapy treatment, and smoking.

·        Pelvic adhesions: Bands of scar tissue that bind organs after pelvic infection, appendicitis, or abdominal or pelvic surgery.

Fig 2: Causes of female infertility

Other causes in women include:

·        Thyroid problems: Disorders of the thyroid gland, either too much thyroid hormone (hyperthyroidism) or too little (hypothyroidism), can interrupt the menstrual cycle or cause infertility.

·        Cancer and its treatment: Certain cancers — particularly female reproductive cancers — often severely impair female fertility. Both radiation and chemotherapy may affect a woman's ability to reproduce.

·        Other conditions: Medical conditions associated with delayed puberty or the absence of menstruation (amenorrhea), such as celiac disease, Cushing's disease, sickle cell disease, kidney disease or diabetes, can affect a woman's fertility. Also genetic abnormalities can make conception and pregnancy less likely.

·        Certain medications: Temporary infertility may occur with the use of certain medications. In most cases, fertility is restored when the medication is stopped.

Risk factors

Many of the risk factors for both male and female infertility are the same. They include the following factors:

·        Age:A woman's fertility gradually declines with age and this decline becomes more pronounced in her mid-30s. Infertility in older women may be due to the number and quality of eggs as they age or to health problems that may interfere with fertility. Men over age 40 may be less fertile than younger men are.

·        Tobacco use: A couple's chance of achieving a pregnancy is reduced if either partner uses tobacco. Smoking also reduces the possible benefit of fertility treatment. Miscarriages are more frequent in women who smoke. Smoking can increase the risk of erectile dysfunction and low sperm count in men.

·        Alcohol use: For women, there is no safe level of alcohol use during conception or pregnancy. Avoid alcohol if you're planning to become pregnant because you may not realize you are pregnant for the first few weeks. Alcohol use increases the risk of birth defects, and it may also make it more difficult to become pregnant. For men, heavy alcohol use can decrease sperm count and motility.

·        Being overweight: Among American women, an inactive lifestyle and being overweight may increase the risk of infertility. In addition, a man's sperm count and testosterone levels may be affected if he is overweight.

·        Being underweight: Women at risk of fertility problems include those with eating disorders, such as anorexia or bulimia, and women who follow a very low calorie or restrictive diet.

·        Exercise issues: Lack of or not enough exercise contributes to obesity, which increases the risk of infertility. Less often, ovulation problems may be associated with frequent strenuous, intense exercise in women who are not overweight.

Tests and diagnosis

Before having infertility testing, be aware of the commitment that is required. Your doctor or clinic will need to determine what your sexual habits are and may make recommendations about changing them. Tests and treatment trial periods may extend over several months.

Evaluation can be expensive and in some cases involves uncomfortable procedures. Many medical plans may not reimburse the cost of fertility treatment. Finally, there's no guarantee — even after all the testing and counseling — that conception will occur.

Tests for men

For a man to be fertile, the testicles must produce enough healthy sperm, and the sperm must be ejaculated effectively into the woman's vagina and be able to travel to and fertilize the egg. Tests for male infertility help to determine whether any of these processes are impaired.

You may have a general physical examination which includes an examination of your genitals. Specific fertility tests may include:

•         Semen analysis: Your doctor may ask for one or more semen specimens. Semen is generally obtained by masturbating or by interrupting intercourse and ejaculating your semen into a clean container. A laboratory analyzes your semen specimen for the health of sperm and the semen fluid.
  

Fig 3: Semen analysis

•              Hormone testing: A blood test to determine the level of testosterone and other male hormones are common.
  
•         Transrectal and scrotal ultrasound: Ultrasound can help your doctor look for evidence of conditions such as retrograde ejaculation and ejaculatory duct obstruction.
  
•         Genetic testing: Genetic testing may be done to determine whether there is a genetic defect causing infertility.                                                                          
  
•         Testicular biopsy: This test involves removing samples from the testicle with a needle. The results of the testicular biopsy will tell if sperm production is normal. If it is, your problem is likely caused by a blockage or sperm transport.
  
•         Other tests: In some cases, other blood or semen tests may be recommended to try to determine why the sperm may not be able to effectively fertilize the egg.

Tests for women

For a woman to be fertile, her ovaries must release healthy eggs. Her reproductive tract must allow an egg to pass into her fallopian tubes and allow the sperm to join the egg for fertilization. The fertilized egg must travel on to the uterus and implant in the lining. Tests for female infertility help to determine whether any of these processes are impaired.

You may have a general physical examination which includes a regular gynecological examination. Specific fertility tests may include:

•         Ovulation testing: A blood test is performed to measure hormone levels to determine whether you're ovulating, if you have not had positive home ovulation tests.
  
•      Hysterosalpingography: It evaluates the condition of uterus and fallopian tubes. X-ray contrast is injected into the uterus, and an X-ray is taken to determine if the cavity is normal and ensure the fluid spills out of fallopian tubes. Blockage or other problems often can be located.
  

Fig 4: Hysterosalpingography

•       Ovarian reserve test: This test helps to determine the quality and quantity of the eggs available for ovulation. This approach often begins with hormone testing early in the menstrual cycle.
  
•         Other hormone tests: Other hormone tests include, checking the levels of ovulatory hormones, as well as thyroid and pituitary hormones that control reproductive processes.
  
•        Imaging tests. Pelvic ultrasound helps to detect uterine or fallopian tube disease. Sometimes a hysterosonography is used to see details inside the uterus that are not seen on a regular ultrasound.
  

Depending on person’s situation, rarely tests may include:

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

Not everyone needs to have all, or even many, of these tests before the cause of infertility is found. Which tests are used and their sequence depend on discussion and agreement between a patient and doctor.

 Treatments and drugs

Treatment of infertility depends on the cause, how long you have been infertile, your age and your partner's age, and many personal preferences. Some causes of infertility can't be corrected. However, a woman may still become pregnant with assisted reproductive technology (ART). Infertility treatment involves significant financial, physical, psychological and time commitment.

Treatment for men

Approaches that involve the male include treatment for general sexual problems or lack of healthy sperm. Treatment may include:

·        Treating infections: Antibiotic treatment may cure an infection of the reproductive tract, but doesn't always restore fertility.

·        Treatments for sexual intercourse problems: Medication or counseling can help to improve fertility in conditions such as erectile dysfunction or premature ejaculation.

·        Hormone treatments and medications: Doctor may recommend hormone replacement or medication in cases where infertility is caused by high or low levels of certain hormones or problems with the way the body uses hormones.

·        Surgery: For example, a varicocele can often be surgically corrected or an obstructed vas deferens repaired. In cases where no sperm are present in the ejaculate, sperm may often be retrieved directly from the testicles.

·        Assisted reproductive technology (ART): ART treatments involve obtaining sperm through normal ejaculation, surgical extraction or from donor individuals, depending on your specific case and wishes. The sperm is then inserted into the female genital tract, or used to perform in vitro fertilization or intra cytoplasmic sperm injection.

Treatment for women

Although a woman may need just one or two therapies to restore fertility, it's possible that several different types of treatment may be needed before she is able to conceive.

·        Stimulating ovulation with fertility drugs: Fertility drugs are the main treatment for women who are infertile due to ovulation disorders. These medications regulate or induce ovulation. Discuss with your doctor about fertility drug options — including the benefits and risks of each type.

·        Intrauterine insemination (IUI): During IUI, healthy sperm that have been collected and concentrated are placed directly in the uterus around the time the woman's ovary releases one or more eggs to be fertilized. Depending on the reasons for infertility, the timing of IUI can be coordinated with normal cycle or with fertility medications.

Fig 5: Intra Uterine Insemination (IUI)

·        Surgery to restore fertility: Uterine problems such as endometrial polyps, a uterine septum or intrauterine scar tissue can be treated with hysteroscopic surgery.

·        Assisted reproductive technology (ART): In vitro fertilization (IVF) is the most common ART technique. IVF involves stimulating and retrieving multiple mature eggs from a woman, fertilizing them with a man's sperm in a dish in a lab, and implanting the embryos in the uterus three to five days after fertilization.

Other techniques are sometimes used in an IVF cycle, such as:

·        Intracytoplasmic sperm injection (ICSI). In ICSI, a single healthy sperm is injected directly into a mature egg. ICSI is often used when semen quality is a problem, there are few sperm, or if fertilization attempts during prior IVF cycles failed.

·        Assisted hatching. This technique attempts to assist the implantation of the embryo into the lining of the uterus by opening the outer covering of the embryo (hatching).

·        Donor eggs or sperm. Most ART is done using the woman's own eggs and her partner's sperm. However, if there are severe problems with either the eggs or sperm, you may choose to use eggs, sperm or embryos from a known or anonymous donor.

·        Gestational carrier. Women who don't have a functional uterus or for whom pregnancy poses a serious health risk might choose IVF using a gestational carrier. In this case, the couple's embryo is placed in the uterus of the carrier for pregnancy.

Complications of treatment

Complications of female infertility treatment may include:

·        Multiple pregnancy: The most common complication of infertility treatment is a multiple pregnancy — twins, triplets or more. Generally, the greater the number of fetuses, the higher the risk of premature labor and delivery. Babies born prematurely are at increased risk of health and developmental problems. The goal of infertility treatment should be a single healthy pregnancy, and preventing multiple pregnancies should be discussed before treatment starts. In some cases, fetal reduction can be used to help a woman deliver fewer babies with lower health risks. Pursuing fetal reduction, however, is a major decision with ethical, emotional and psychological consequences.

·        Ovarian hyper stimulation syndrome (OHSS): Use of injectable fertility drugs to induce ovulation can cause OHSS, in which the ovaries become swollen and painful. Symptoms may include mild abdominal pain, bloating and nausea that last about a week, or longer if you become pregnant. Rarely, a more severe form causes rapid weight gain and shortness of breath requiring emergency treatment.

·        Bleeding or infection: As with any invasive procedure, there is a rare risk of bleeding or infection with assisted reproductive technology.

·        Premature delivery or low birth weight: The greatest risk factor for low birth weight is a multiple fetus pregnancy. In single live births, there may be a greater chance of preterm delivery or low birth weight associated with IVF.

·        Birth defects: Some research suggests that babies conceived using IVF might be at increased risk of certain birth defects, such as heart and digestive problems and cleft lip or cleft palate.

Complications of male infertility treatment are rare and may occur following surgery including infection, bruising, or lack of efficacy with the procedure.

Prevention

Some types of infertility cannot be prevented. But several strategies may increase the chances of pregnancy. They are:

Couples

For couples, having regular intercourse several times around the time of ovulation offers the highest pregnancy rate. Intercourse occurring several days before and until a day after ovulation improves the probability of pregnancy. This is usually at the middle of the cycle halfway between menstrual periods for most women with menstrual cycles 28 days apart.

Men

For men, although most types of infertility are not preventable, the following strategies may help:

·        Avoid drug and tobacco use and excessive alcohol consumption, which may contribute to male infertility.

·        Avoid high temperatures as this can affect sperm production and motility. Although this effect is usually temporary, avoid hot tubs and steam baths.

·        Avoid exposure to industrial or environmental toxins,which can impact sperm production.

·        Limit medications that may impact fertility, both prescribed and nonprescription drugs. Talk with your doctor about any medications you take regularly, but don't stop taking prescribed medications without medical advice.

·        Exercise regularly, eat a balanced diet, and maintain a healthy weight. Obesity is directly related to testosterone levels, which is a key hormone responsible for sperm production. Eating a balanced diet provides the necessary nutrients to optimize sperm function and minimize the effects of factors which may otherwise damage sperm.

·        Treating reversible causes, such as a varicocele (dilated veins of the spermatic cord- refer fig. 6) frequently improves sperm numbers and quality and may help to prevent further loss of fertility.

Fig 6: Varicocele

Women

For women, a number of strategies may increase the chances of becoming pregnant:

•           Exercise moderately. Regular exercise is important, but if you're exercising so intensely that your periods are infrequent or absent, your fertility may be impaired.
  
•          Avoid weight extremes. Being overweight or underweight can affect your hormone production and cause infertility.
  
•          Quit smoking. Tobacco has multiple negative effects on fertility, not to mention your general health and the health of a fetus. If you smoke and are considering pregnancy, quit immediately.
  
•           Avoid alcohol and street drugs. These substances may impair your ability to conceive and have a healthy pregnancy. Don't drink alcohol or use illegal drugs, such as marijuana or cocaine.
  
•           Limit medications that may impact fertility. The use of some prescribed and nonprescription drugs can decrease the chance of getting pregnant or keeping a pregnancy. Talk with your doctor about any medications you take regularly, but don't stop taking prescribed medications without medical advice.
  
•      Limit caffeine. Women trying to get pregnant may want to limit caffeine intake. Ask your doctor for guidance on safe use of caffeine.