Major causes of infertility

Below I will present you some of the most common troubles to get pregnant for women and men

Endometriosis

Endometriosis is a hormonal and immune system disease in which cells similar to that which line the uterus (endometrium) grow outside the uterine cavity, most commonly on the membrane which lines the abdominal cavity, the peritoneum. The uterine cavity is lined with endometrial cells, which are under the influence of female hormones. Endometrial cells in areas outside the uterus are also influenced by hormonal changes and respond in a way that is similar to the cells found inside the uterus. Common symptoms of endometriosis are pain and infertility. The pain often is worse with the menstrual cycle and is the most common cause of secondary dysmenorrhea.

Endometriosis is typically diagnosed during the reproductive years, but has been diagnosed in girls as young as 8 and has been found to continue past menopause; it has been estimated that endometriosis occurs in roughly 4–10% of women.^[1] Symptoms may depend on the site of active endometriosis. Its main but not universal symptom is pelvic pain in various manifestations. There is an established association between endometriosis and infertility.^[1] Endometriosis has a significant social and psychological impact.^[2]

There is no cure for endometriosis, but it can be treated in a variety of ways, including pain medication, hormonal treatments, and surgery.^[3]

Signs and symptoms

Pelvic pain

A major symptom of endometriosis is recurring pelvic pain. The pain can range from mild to severe cramping or stabbing pain that occurs on both sides of the pelvis, in the lower back and rectal area, and even down the legs. The amount of pain a woman feels correlates poorly with the extent or stage (1 through 4) of endometriosis, with some women having little or no pain despite having extensive endometriosis or endometriosis with scarring, while other women may have severe pain even though they have only a few small areas of endometriosis.^[4] Symptoms of endometriosis-related pain may include:^[5]

• dysmenorrhea – painful, sometimes disabling cramps during the menstrual period; pain may get worse over time (progressive pain), also lower back pains linked to the pelvis
• chronic pelvic pain – typically accompanied by lower back pain or abdominal pain
• dyspareunia – painful sex
• dysuria – urinary urgency, frequency, and sometimes painful voiding

Throbbing, gnawing, and dragging pain to the legs are reported more commonly by women with endometriosis.^[6] Compared with women with superficial endometriosis, those with deep disease appear to be more likely to report shooting rectal pain and a sense of their insides being pulled down.^[6] Individual pain areas and pain intensity appears to be unrelated to the surgical diagnosis, and the area of pain unrelated to area of endometriosis.^[6]
Endometriosis lesions react to hormonal stimulation and may "bleed" at the time of menstruation. The blood accumulates locally, causes swelling, and triggers inflammatory responses with the activation of cytokines. This process may cause pain. Pain can also occur from adhesions (internal scar tissue) binding internal organs to each other, causing organ dislocation. Fallopian tubes, ovaries, the uterus, the bowels, and the bladder can be bound together in ways that are painful on a daily basis, not just during menstrual periods.^[7]
Also, endometriotic lesions can develop their own nerve supply, thereby creating a direct and two-way interaction between lesions and the central nervous system, potentially producing a variety of individual differences in pain that can, in some women, become independent of the disease itself.^[4]

Infertility

Main article: Endometriosis and infertility

Many women with infertility may have endometriosis. Among women with endometriosis, up to 30% to 50% may experience infertility.^[8]

Other

Other symptoms include diarrhea or constipation,^[6] chronic fatigue,^[9] nausea and vomiting, headaches, low-grade fevers, heavy and/or irregular periods, and hypoglycemia.^[10]
In addition to pain during menstruation, the pain of endometriosis can occur at other times of the month. There can be pain with ovulation, pain associated with adhesions, pain caused by inflammation in the pelvic cavity, pain during bowel movements and urination, during general bodily movement like exercise, pain from standing or walking, and pain with intercourse. But the most desperate pain is usually with menstruation and many women dread having their periods. Pain can also start a week before a menstrual period, during and even a week after a menstrual period, or it can be constant. The pain can be debilitating and the emotional stress can take a toll.^[11]
Current research has demonstrated an association between endometriosis and certain types of cancers, notably some types of ovarian cancer,^[12][13] non-Hodgkin's lymphoma and brain cancer.^[14] Despite similarities in their name and location, endometriosis bears no relationship to endometrial cancer.^[15]
Endometriosis often also coexists with leiomyoma or adenomyosis, but studies that look into similarities and differences between endometriosis and adenomyosis have conflicting results.^[16] A 1988 survey conducted in the United States found significantly more hypothyroidism, fibromyalgia, chronic fatigue syndrome, autoimmune diseases, allergies and asthma in women with endometriosis compared to the general population.^[17]

Complications

Complications of endometriosis include internal scarring, adhesions, pelvic cysts, chocolate cyst of ovaries, ruptured cysts, and bowel and ureteral obstruction resulting from pelvic adhesions.^[18] Endometriosis-associated infertility can be related to scar formation and anatomical distortions due to the endometriosis.
Ovarian endometriosis may complicate pregnancy by decidualization, abscess and/or rupture.^[19]
Pleural implantations are associated with recurrent right pneumothoraces at times of a menstrual period, termed catamenial pneumothorax.^[20]

Aging

Aging brings with it many effects that may reduce fertility. Depletion over time of ovarian follicles affects menstrual regularity. Endometriosis has more time to produce scarring of the ovary and tubes so they cannot move freely or it can even replace ovarian follicular tissue if ovarian endometriosis persists and grows. Leiomyomata (fibroids) can slowly grow and start causing endometrial bleeding that disrupts implantation sites or distorts the endometrial cavity which affects carrying a pregnancy in the very early stages. Abdominal adhesions from other intraabdominal surgery, or ruptured ovarian cysts can also affect tubal motility needed to sweep the ovary and gather an ovulated follicle (egg).
Incidences of endometriosis have occurred in postmenopausal women,^[34] and in less common cases, girls may have endometriosis symptoms before they even reach menarche.^[35][36]

Diagnosis

A health history and a physical examination can lead the health care practitioner to suspect endometriosis. Although doctors can often feel the endometrial growths during a pelvic exam, and these symptoms may be signs of endometriosis, diagnosis cannot be confirmed by exam only. Use of pelvic ultrasound may identify large endometriotic cysts (called endometriomas). However, smaller endometriosis implants cannot be visualized with ultrasound technique.

Laparoscopy

Laparoscopy, a surgical procedure where a camera is used to look inside the abdominal cavity, is the only way to officially diagnose endometriosis as it permits lesion visualization, unless the lesion is visible externally, e.g. an endometriotic nodule in the vagina. If the growths are not visible, a biopsy may be taken to determine the diagnosis.^[54] Surgery for diagnoses also allows for surgical treatment of endometriosis at the same time.
To the eye, lesions can appear dark blue, powder-burn black, red, white, yellow, brown or non-pigmented. Lesions vary in size. Some within the pelvis walls may not be visible, as normal-appearing peritoneum of infertile women reveals endometriosis on biopsy in 6–13% of cases.^[55] Early endometriosis typically occurs on the surfaces of organs in the pelvic and intra-abdominal areas. Health care providers may call areas of endometriosis by different names, such as implants, lesions, or nodules. Larger lesions may be seen within the ovaries as endometriomas or "chocolate cysts", "chocolate" because they contain a thick brownish fluid, mostly old blood.
Frequently during diagnostic laparoscopy, no lesions are found in women with chronic pelvic pain, a symptom common to other disorders including adenomyosis, pelvic adhesions, pelvic inflammatory disease, congenital anomalies of the reproductive tract, and ovarian or tubal masses.^[56]

Staging

Surgically, endometriosis can be staged I–IV (Revised Classification of the American Society of Reproductive Medicine).^[57] The process is a complex point system that assesses lesions and adhesions in the pelvic organs, but it is important to note staging assesses physical disease only, not the level of pain or infertility. A person with Stage I endometriosis may have little disease and severe pain, while a person with Stage IV endometriosis may have severe disease and no pain or vice versa. In principle the various stages show these findings:

http://en.wikipedia.org/wiki/Endometriosis

Problems With Ovulation

The ovaries do not release an egg each month (see see Menstrual Cycle).

• Ovulation problems can result from dysfunction of the part of the brain and the glands that control ovulation or dysfunction of the ovaries.
• Women can determine whether ovulation is occurring and estimate when it occurs by measuring body temperature or using home predictor kits.
• Doctors use ultrasonography or blood or urine tests to evaluate ovulation problems.
• Drugs, usually clomiphene
  , can often stimulate ovulation, but pregnancy does not always follow.

In women, a common cause of infertility is an ovulation problem.

Causes

Reproduction is controlled by a system that includes the hypothalamus (an area of the brain), pituitary gland, ovaries, and other glands, such as the adrenal glands and thyroid gland. Ovulation problems result when one part of this system malfunctions. For example,

• The hypothalamus may not secrete gonadotropin-releasing hormone, which stimulates the pituitary gland to produce the hormones that stimulate the ovaries to trigger ovulation (luteinizing hormone and follicle-stimulating hormone).
• The pituitary gland may produce too little luteinizing hormone or follicle-stimulating hormone.
• The ovaries may produce too little estrogen.
• The pituitary gland may produce too much prolactin, a hormone that stimulates milk production. High levels of prolactin (hyperprolactinemia) may result in low levels of the hormones that trigger ovulation. Prolactin levels may be high because of a pituitary gland tumor (prolactinoma), which is almost always noncancerous.
• Other glands may malfunction. For example, the adrenal glands may overproduce male hormones (such as testosterone), or the thyroid glands can overproduce or underproduce thyroid hormones, which help keep the pituitary gland and ovaries in balance.

Ovulation problems may be due to many disorders. One of the most common causes is polycystic ovary syndrome, which is usually characterized by excess weight and excess production of male hormones by the ovaries. Other causes include diabetes and obesity. Problems may also result from excessive exercise, certain drugs (such as estrogens and progestins and antidepressants), weight loss, or psychologic stress. Sometimes the cause is early menopause—when the supply of eggs runs out early.

An ovulation problem is often the cause of infertility in women who have irregular periods or no periods (amenorrhea—see see Absence of Menstrual Periods). Infrequently, an ovulation problem is the cause of infertility in women who have regular menstrual periods but do not have premenstrual symptoms, such as breast tenderness, lower abdominal swelling, and mood changes.

Diagnosis

Doctors ask women to describe their menstrual periods (menstrual history—see What the doctor does). Based on this information, doctors may be able to determine whether women are ovulating.

To determine if or when ovulation is occurring, doctors may ask a woman to take her temperature at rest (basal body temperature) each day. If possible, she should use a basal body temperature thermometer (which is highly accurate) or, if it is unavailable, a mercury thermometer. Electronic thermometers are the least accurate. Usually, the best time is immediately after awakening. A decrease in basal body temperature suggests that ovulation is about to occur. An increase of more than 0.9° F (0.5° C) in temperature usually indicates that ovulation has just occurred. However, this method is inconvenient for many women and is not reliable or precise. At best, it predicts ovulation only within 2 days. A more accurate method is an ovulation predictor kit for use at home. This kit detects an increase in luteinizing hormone in the urine 24 to 36 hours before ovulation. Urine is tested on several consecutive days.

Doctors can accurately determine whether and when ovulation occurs. Methods include ultrasonography and measurement of the level of progesterone in the blood or saliva or the level of one of its by-products in the urine. A marked increase in these levels indicates that ovulation has occurred.

Doctors may do other tests to check for disorders that can cause ovulation problems. For example, they may measure testosterone levels in the blood to check for polycystic ovary syndrome.

Treatment

A drug to trigger ovulation, such as clomiphene
, aromatase inhibitors, or human gonadotropins, may be used. The particular drug is selected based on the specific problem. If the cause of infertility is early menopause, neither clomiphene
 nor human gonadotropins can stimulate ovulation.

Clomiphene:

If ovulation has not occurred for a long time, clomiphene
 is usually preferred. A few days after menstrual bleeding begins, the woman takes clomiphene
 by mouth for 5 days. Usually, she ovulates 5 to 10 days after clomiphene
 is stopped, and she has a menstrual period 14 to 16 days after ovulation.Clomiphene
 is not effective for all causes of ovulation problems. It is most effective when the cause is polycystic ovary syndrome.

If a woman does not have a period after treatment with clomiphene
, she takes a pregnancy test. If she is not pregnant, the treatment cycle is repeated. A higher dose of clomiphene
 is used in each cycle until ovulation occurs or the maximum dose is reached. When the dose that triggers ovulation is determined, the woman takes that dose for at least three or four more treatment cycles. Most women who become pregnant do so by the fourth cycle in which ovulation occurs. Although about 75 to 80% of women treated with clomiphene
 ovulate, only about 40 to 50% of those who ovulate become pregnant. About 5% of pregnancies in women treated with clomiphene
 involve more than one fetus, primarily twins.

Side effects of clomiphene
 include hot flashes, abdominal bloating, breast tenderness, nausea, vision problems, and headaches. Fewer than 1% of women treated with clomiphene
 develop ovarian hyperstimulation syndrome. In this syndrome, the ovaries enlarge greatly and a large amount of fluid moves out the bloodstream into the abdomen. This syndrome may be life threatening. To try to prevent it, doctors prescribe the lowest effective dose of clomiphene
, and if the ovaries enlarge, they stop the drug.

Aromatase inhibitors:

Aromatase inhibitors (such as letrozole
) are usually used to treat breast cancer in women who have gone through menopause. But they may also be used to trigger ovulation when clomiphene
 does not work. These drugs have fewer side effects than clomiphene
. However, these drugs are not yet considered standard treatment for ovulation problems. Birth defects of the genitals have occurred in fetuses of women who took an aromatase inhibitor during the pregnancy, so these drugs are used only after pregnancy has been ruled out.

Human gonadotropins:

If a woman does not ovulate or become pregnant during treatment with clomiphene
 or an aromatase inhibitor, hormonal therapy with human gonadotropins, injected into a muscle or under the skin, can be tried. Human gonadotropins stimulate the follicles of the ovaries to mature. Follicles are fluid-filled cavities, each of which contains an egg (see see Fallopian tubes). Ultrasonography can detect when the follicles are mature. Then, the woman is given an injection of a different hormone, human chorionic gonadotropin, to trigger ovulation. When human gonadotropins are used appropriately, more than 95% of women treated with them ovulate, but only 50 to 75% of those who ovulate become pregnant. About 10 to 30% of pregnancies in women treated with human gonadotropins involve more than one fetus, primarily twins.

Human gonadotropins are expensive and can have severe side effects, so doctors closely monitor the woman during treatment. About 10 to 20% of women treated with human gonadotropins develop ovarian hyperstimulation syndrome. If hyperstimulation occurs, doctors may not give the woman human chorionic gonadotropin to trigger ovulation.

Other drugs:

If the hypothalamus does not secrete gonadotropin-releasing hormone, a synthetic version of this hormone (called gonadorelin
 acetate), given intravenously, may be useful. This drug, like the natural hormone, stimulates the pituitary gland to produce the hormones that trigger ovulation. The risk of ovarian hyperstimulation is low with this treatment, so close monitoring is not needed. However, this drug is not available in the United States.

When the cause of infertility is high levels of the hormone prolactin, the best drug to use is one that acts like dopamine
, called a dopamine
 agonist, such as bromocriptine
 or cabergoline
. (Dopamine
is a chemical messenger that generally inhibits the production of prolactin.)

http://www.merckmanuals.com/home/womens_health_issues/infertility/problems_with_ovulation.html

Polycystic ovary syndrome (PCOS) 

• What is polycystic ovary syndrome (PCOS)?
• How many women have PCOS?
• What causes PCOS?
• What are the symptoms of PCOS?
• Why do women with PCOS have trouble with their menstrual cycle and fertility?
• Does PCOS change at menopause?
• How do I know if I have PCOS?
• How is PCOS treated?
• How does PCOS affect a woman while pregnant?
• Does PCOS put women at risk for other health problems?
• I have PCOS. What can I do to prevent complications?
• How can I cope with the emotional effects of PCOS?
• More information on polycystic ovary syndrome (PCOS)

What is polycystic ovary syndrome (PCOS)?

Polycystic (pah-lee-SIS-tik) ovary syndrome (PCOS) is a health problem that can affect a woman's:

• Menstrual cycle
• Ability to have children
• Hormones
• Heart
• Blood vessels
• Appearance

With PCOS, women typically have:

• High levels of androgens (AN-druh-junz). These are sometimes called male hormones, though females also make them.
• Missed or irregular periods (monthly bleeding)
• Many small cysts (sists) (fluid-filled sacs) in their ovaries

Between 1 in 10 and 1 in 20 women of childbearing age has PCOS. As many as 5 million women in the United States may be affected. It can occur in girls as young as 11 years old.How many women have PCOS?

The cause of PCOS is unknown. But most experts think that several factors, including genetics, could play a role. Women with PCOS are more likely to have a mother or sister with PCOS.What causes PCOS?

A main underlying problem with PCOS is a hormonal imbalance. In women with PCOS, the ovaries make more androgens than normal. Androgens are male hormones that females also make. High levels of these hormones affect the development and release of eggs during ovulation.

Researchers also think insulin may be linked to PCOS. Insulin is a hormone that controls the change of sugar, starches, and other food into energy for the body to use or store. Many women with PCOS have too much insulin in their bodies because they have problems using it. Excess insulin appears to increase production of androgen. High androgen levels can lead to:

• Acne
• Excessive hair growth
• Weight gain
• Problems with ovulation

The symptoms of PCOS can vary from woman to woman. Some of the symptoms of PCOS include:What are the symptoms of PCOS?

• Infertility (not able to get pregnant) because of not ovulating. In fact, PCOS is the most common cause of female infertility.
• Infrequent, absent, and/or irregular menstrual periods
• Hirsutism (HER-suh-tiz-um) — increased hair growth on the face, chest, stomach, back, thumbs, or toes
• Cysts on the ovaries
• Acne, oily skin, or dandruff
• Weight gain or obesity, usually with extra weight around the waist
• Male-pattern baldness or thinning hair
• Patches of skin on the neck, arms, breasts, or thighs that are thick and dark brown or black
• Skin tags — excess flaps of skin in the armpits or neck area
• Pelvic pain
• Anxiety or depression
• Sleep apnea — when breathing stops for short periods of time while asleep

The ovaries, where a woman’s eggs are produced, have tiny fluid-filled sacs called follicles or cysts. As the egg grows, the follicle builds up fluid. When the egg matures, the follicle breaks open, the egg is released, and the egg travels through thefallopian tube to the uterus (womb) for fertilization. This is called ovulation.Why do women with PCOS have trouble with their menstrual cycle and fertility?

In women with PCOS, the ovary doesn't make all of the hormones it needs for an egg to fully mature. The follicles may start to grow and build up fluid but ovulation does not occur. Instead, some follicles may remain as cysts. For these reasons, ovulation does not occur and the hormone progesterone is not made. Without progesterone, a woman's menstrual cycle is irregular or absent. Plus, the ovaries make male hormones, which also prevent ovulation.

Normal ovary and polycystic ovary

Yes and no. PCOS affects many systems in the body. So, many symptoms may persist even though ovarian function and hormone levels change as a woman nears menopause. For instance, excessive hair growth continues, and male-pattern baldness or thinning hair gets worse after menopause. Also, the risks of complications (health problems) from PCOS, such as heart attack, stroke, and diabetes, increase as a woman gets older.Does PCOS change at menopause?

There is no single test to diagnose PCOS. Your doctor will take the following steps to find out if you have PCOS or if something else is causing your symptoms.How do I know if I have PCOS?

Medical history. Your doctor will ask about your menstrual periods, weight changes, and other symptoms.

Physical exam. Your doctor will want to measure your blood pressure, body mass index (BMI), and waist size. He or she also will check the areas of increased hair growth. You should try to allow the natural hair to grow for a few days before the visit.

Pelvic exam. Your doctor might want to check to see if your ovaries are enlarged or swollen by the increased number of small cysts.

Blood tests. Your doctor may check the androgen hormone and glucose (sugar) levels in your blood.

Vaginal ultrasound (sonogram). Your doctor may perform a test that uses sound waves to take pictures of the pelvic area. It might be used to examine your ovaries for cysts and check the endometrium (en-do-MEE-tree-uhm) (lining of the womb). This lining may become thicker if your periods are not regular.

Because there is no cure for PCOS, it needs to be managed to prevent problems. Treatment goals are based on your symptoms, whether or not you want to become pregnant, and lowering your chances of getting heart disease and diabetes. Many women will need a combination of treatments to meet these goals. Some treatments for PCOS include:How is PCOS treated?

Lifestyle modification. Many women with PCOS are overweight or obese, which can cause health problems. You can help manage your PCOS by eating healthy and exercising to keep your weight at a healthy level. Healthy eating tips include:

• Limiting processed foods and foods with added sugars
• Adding more whole-grain products, fruits, vegetables, and lean meats to your diet

This helps to lower blood glucose (sugar) levels, improve the body's use of insulin, and normalize hormone levels in your body. Even a 10 percent loss in body weight can restore a normal period and make your cycle more regular.

Birth control pills. For women who don't want to get pregnant, birth control pills can:

• Control menstrual cycles
• Reduce male hormone levels
• Help to clear acne

Keep in mind that the menstrual cycle will become abnormal again if the pill is stopped. Women may also think about taking a pill that only has progesterone (proh-JES-tuh-rohn), like Provera, to control the menstrual cycle and reduce the risk of endometrial cancer (See Does PCOS put women at risk for other health problems?). But, progesterone alone does not help reduce acne and hair growth.

Diabetes medications. The medicine metformin (Glucophage) is used to treat type 2 diabetes. It has also been found to help with PCOS symptoms, though it isn’t approved by the U.S Food and Drug Administration (FDA) for this use. Metformin affects the way insulin controls blood glucose (sugar) and lowers testosterone production. It slows the growth of abnormal hair and, after a few months of use, may help ovulation to return. Recent research has shown metformin to have other positive effects, such as decreased body mass and improved cholesterol levels. Metformin will not cause a person to become diabetic.

Fertility medications. Lack of ovulation is usually the reason for fertility problems in women with PCOS. Several medications that stimulate ovulation can help women with PCOS become pregnant. Even so, other reasons for infertility in both the woman and man should be ruled out before fertility medications are used. Also, some fertility medications increase the risk for multiple births (twins, triplets). Treatment options include:

• Clomiphene (KLOHM-uh-feen) (Clomid, Serophene) — the first choice therapy to stimulate ovulation for most patients.
• Metformin taken with clomiphene — may be tried if clomiphene alone fails. The combination may help women with PCOS ovulate on lower doses of medication.
• Gonadotropins (goe-NAD-oh-troe-pins) — given as shots, but are more expensive and raise the risk of multiple births compared to clomiphene.

Another option is in vitro fertilization (IVF). IVF offers the best chance of becoming pregnant in any given cycle. It also gives doctors better control over the chance of multiple births. But, IVF is very costly.

Surgery. "Ovarian drilling" is a surgery that may increase the chance of ovulation. It’s sometimes used when a woman does not respond to fertility medicines. The doctor makes a very small cut above or below the navel (belly button) and inserts a small tool that acts like a telescope into the abdomen (stomach). This is called laparoscopy (lap-uh-RAHS-kuh-pee). The doctor then punctures the ovary with a small needle carrying an electric current to destroy a small portion of the ovary. This procedure carries a risk of developing scar tissue on the ovary. This surgery can lower male hormone levels and help with ovulation. But, these effects may only last a few months. This treatment doesn't help with loss of scalp hair or increased hair growth on other parts of the body.

Medicine for increased hair growth or extra male hormones. Medicines called anti-androgens may reduce hair growth and clear acne. Spironolactone (speer-on-oh-LAK-tone) (Aldactone), first used to treat high blood pressure, has been shown to reduce the impact of male hormones on hair growth in women. Finasteride (fin-AST-uhr-yd) (Propecia), a medicine taken by men for hair loss, has the same effect. Anti-androgens are often combined with birth control pills.  These medications should not be taken if you are trying to become pregnant.

Before taking Aldactone, tell your doctor if you are pregnant or plan to become pregnant. Do not breastfeed while taking this medicine. Women who may become pregnant should not handle Propecia.

Other options include:

• Vaniqa (van-ik-uh) cream to reduce facial hair
• Laser hair removal or electrolysis to remove hair
• Hormonal treatment to keep new hair from growing

Other treatments. Some research has shown that bariatric (weight loss) surgery may be effective in resolving PCOS in morbidly obese women. Morbid obesity means having a BMI of more than 40, or a BMI of 35 to 40 with an obesity-related disease. The drug troglitazone (troh-GLIT-uh-zohn) was shown to help women with PCOS. But, it was taken off the market because it caused liver problems. Similar drugs without the same side effect are being tested in small trials.

Researchers continue to search for new ways to treat PCOS. To learn more about current PCOS treatment studies, visitClinicalTrials.gov. Talk to your doctor about whether taking part in a clinical trial might be right for you.

How does PCOS affect a woman while pregnant?

Women with PCOS appear to have higher rates of:

• Miscarriage
• Gestational diabetes
• Pregnancy-induced high blood pressure (preeclampsia)
• Premature delivery

Babies born to women with PCOS have a higher risk of spending time in a neonatal intensive care unit or of dying before, during, or shortly after birth. Most of the time, these problems occur in multiple-birth babies (twins, triplets).

Researchers are studying whether the diabetes medicine metformin can prevent or reduce the chances of having problems while pregnant. Metformin also lowers male hormone levels and limits weight gain in women who are obese when they get pregnant.

Metformin is an FDA pregnancy category B drug. It does not appear to cause major birth defects or other problems in pregnant women. But, there have only been a few studies of metformin use in pregnant women to confirm its safety. Talk to your doctor about taking metformin if you are pregnant or are trying to become pregnant. Also, metformin is passed through breastmilk. Talk with your doctor about metformin use if you are a nursing mother.

Women with PCOS have greater chances of developing several serious health conditions, including life-threatening diseases. Recent studies found that:Does PCOS put women at risk for other health problems?

• More than 50 percent of women with PCOS will have diabetes or pre-diabetes (impaired glucose tolerance) before the age of 40.
• The risk of heart attack is 4 to 7 times higher in women with PCOS than women of the same age without PCOS.
• Women with PCOS are at greater risk of having high blood pressure.
• Women with PCOS have high levels of LDL (bad) cholesterol and low levels of HDL (good) cholesterol.
• Women with PCOS can develop sleep apnea. This is when breathing stops for short periods of time during sleep.

Women with PCOS may also develop anxiety and depression. It is important to talk to your doctor about treatment for these mental health conditions.

Women with PCOS are also at risk for endometrial cancer. Irregular menstrual periods and the lack of ovulation cause women to produce the hormone estrogen, but not the hormone progesterone. Progesterone causes the endometrium (lining of the womb) to shed each month as a menstrual period. Without progesterone, the endometrium becomes thick, which can cause heavy or irregular bleeding. Over time, this can lead to endometrial hyperplasia, when the lining grows too much, and cancer.

I have PCOS. What can I do to prevent complications?

If you have PCOS, get your symptoms under control at an earlier age to help reduce your chances of having complications like diabetes and heart disease. Talk to your doctor about treating all your symptoms, rather than focusing on just one aspect of your PCOS, such as problems getting pregnant. Also, talk to your doctor about getting tested for diabetes regularly. Other steps you can take to lower your chances of health problems include:

• Eating right
• Exercising
• Not smoking

Having PCOS can be difficult. You may feel:How can I cope with the emotional effects of PCOS?

• Embarrassed by your appearance
• Worried about being able to get pregnant
• Depressed

Getting treatment for PCOS can help with these concerns and help boost your self-esteem. You may also want to look for support groups in your area or online to help you deal with the emotional effects of PCOS. You are not alone and there are resources available for women with PCOS.

http://www.merckmanuals.com/home/womens_health_issues/infertility/problems_with_ovulation.html

Fallopian tube obstruction

Fallopian tube obstruction is a major cause of female infertility. Blockedfallopian tubes are unable to let the ovum and the sperm converge, thus making fertilization impossible. Fallopian Tubes are also known as oviducts, uterine tubes, and salpinges (singular salpinx).

Types

Approximately 20% of female infertility can be attributed to tubal causes.^[1] Distal tubal occlusion (affecting the end towards the ovary) is typically associated with hydrosalpinx formation and often caused by Chlamydia trachomatis.^[1] Pelvic adhesions may be associated with such an infection. In less severe forms, the fimbriae may be aggluntinated and damaged, but some patency may still be preserved. Midsegment tubal obstruction can be due to tubal ligation procedures as that part of the tube is a common target of sterilization interventions. Proximal tubal occlusion can occur after infection such as a septic abortion. Also, some tubal sterilization procedures such as the Essure procedure target the part of the tube that is near the uterus..

§Causes

Most commonly a tube may be obstructed due to infection such as pelvic inflammatory disease (PID). The rate of tubal infertility has been reported to be 12% after one, 23% after two, and 53% after three episodes of PID.^[1] The Fallopian tubes may also be occluded or disabled by endometritis, infections after childbirth and intraabdominal infections includingappendicitis and peritonitis. The formation of adhesions may not necessarily block a fallopian tube, but render it dysfunctional by distorting or separating it from the ovary. It has been reported that women with distal tubal occlusion have a higher rate of HIV infection.^[2]

Fallopian tubes may be blocked as a method of contraception. In these situations tubes tend to be healthy and typically patients requesting the procedure had children. Tubal ligation is considered a permanent procedure.

§Evaluation

While a full testing of tubal functions in patients with infertility is not possible, testing of tubal patency is feasible. Ahysterosalpingogram will demonstrate that tubes are open when the radioopaque dye spills into the abdominal cavity.Sonography can demonstrate tubal abnormalities such as a hydrosalpinx indicative of tubal occlusion. During surgery, typically laparoscopy, the status of the tubes can be inspected and a dye such as methylene blue can be injected in a process termed chromotubation into the uterus and shown to pass through the tubes when the cervix is occluded. Laparoscopic chromotubation has been described as the gold standard of tubal evaluation.^[3] As tubal disease is often related to Chlamydia infection, testing for Chlamydia antibodies has become a cost-effective screening device for tubal pathology.^[3]

Tubal insufflation is only of historical interest as an older office method to indicate patency;^[4] it was used prior to laparoscopic evaluation of pelvic organs.

§Treatment

Treatment of fallopian tube obstruction has traditionally been treated with fallopian tubal surgery (tuboplasty) with a goal of restoring patency to the tubes and thus possibly normal function. A common modern day method of treatment is in vitro fertilization as it is more cost-effective, less invasive, and results are immediate. Alternative methods such as manual physical therapy are also cited for the ability to open and return function to blocked fallopian tubes in some women. Treatments such as assisted reproductive technologies are used more often than surgery.^[5]

§Tuboplasty

Main article: Tuboplasty

Tuboplasty refers to a number of surgical operations that attempt to restore patency and functioning of the Fallopian tube(s) so that a pregnancy could be achieved. As tubal infertility is a common cause of infertility, tuboplasties were commonly performed prior to the development of effective in vitro fertilization (IVF).

Different types of tuboplasty have been developed and can be applied by laparoscopy or laparotomy.^[6] They include lysis of adhesions,^[7] fimbrioplasty (repairing the fimbriated end of the tubes),^[8] salpinostomy (creating an opening for the tube), resection and reananstomosis (removing a piece of blocked tube and reuniting the remaining patent parts of the tube), and tubal reimplantation (reconnecting the tube to the uterus). Further, using fluoroscopy or hysteroscopy proximal tubal occlusion can be overcome by unilateral or bilateral selective tubal cannulation, a procedure where a thin catheter is advanced through the proximal portion of the fallopian tube os to examine and possibly restore tubal patency^[8]salpinostomy (creating an opening for the tube)^[9] or falloposcopy.

Results of tubal surgery are inversely related to damage that exists prior to surgery.^[10] Development of adhesions remains a problem.^[1] Patients with operated tubes are at increased risk for ectopic pregnancy.,^[10] although in vitro fertiliztion in patients with damaged tubes is also associated with a risk for ectopic pregnancy.

§In vitro fertilization

Main article: In vitro fertilization

In vitro fertilisation is a process by which an egg is fertilised by sperm outside the body: in vitro. IVF is a major treatment forinfertility when other methods of assisted reproductive technology have failed. The process involves monitoring a woman's ovulatory process, removing ovum or ova (egg or eggs) from the woman's ovaries and letting sperm fertilise them in a fluid medium in a laboratory. When a woman's natural cycle is monitored to collect a naturally selected ovum (egg) for fertilisation, it is known as natural cycle IVF. The fertilised egg (zygote) is then transferred to the patient's uterus with the intention of establishing a successful pregnancy.

While IVF therapy has largely replaced tubal surgery in the treatment of infertility, the presence of hydrosalpinx is a detriment to IVF success.^[5] It has been recommended that prior to IVF, laparoscopic surgery should be done to either block or remove hydrosalpinges.^[11]

Alternative medicine

For fallopian tube obstruction, alternative medicine has been used as a form of fertility treatment.^[12] A study of the use of alternative methods showed that only a minority of infertile couples utilize such treatments.^[12] It also showed that alternative methods are more often chosen by couples who were wealthier, have not yet achieved pregnancy, or had a belief in the effectiveness of such treatments.^[12] Of the study participants, 29% used a CAM modality for treatment, 22% used acupuncture, 17% used herbal therapies, and 1% using meditation.^[12]

http://en.wikipedia.org/wiki/Fallopian_tube_obstruction

Infertility in men

Causes of male infertility

The major causes of male infertility are:

• Obstructions to the passage of sperm
• Problems with sperm (such as low sperm count)
• Functional problems (such as impotence)
• Hormonal problems.

Obstructions causing infertility in men

Sperm are made in the testicles, then they spend two to ten days passing through a series of small tubes called the epididymis where they mature and exit into a larger tube called the vas deferens. The vas deferens empties the sperm into the ejaculatory duct, where they are mixed with seminal fluid from the seminal vesicles and the prostate gland. 

During ejaculation, muscular contractions force the semen into the urethra and out of the penis. Blockages or absences of tubes (including the vas deferens) are the cause of around one in three cases of male infertility. Blockages or absences of tubes may be due to vasectomy or injury.

Problems with sperm causing infertility in men

Problems with sperm numbers or quality are thought to be caused by genetic factors. Tiny fragments of the male chromosome may be missing in some men with sperm problems. This may cause:

• Absent sperm (azoospermia) – the semen doesn’t contain any sperm. This may be caused by a blockage of the tubes or testicular failure
• Low sperm count (oligospermia) – the ejaculate has insufficient sperm to bring about conception
• Abnormal shape – a healthy sperm is shaped like a streamlined tadpole. Abnormally shaped sperm may have problems penetrating the surface of the woman’s egg
• Poor motility – a healthy sperm has a lashing tail which helps it to swim through the woman’s reproductive system. Sperm with poor motility may swim feebly or not at all.

Functional problems causing infertility in men

Functional problems that can cause or contribute to male infertility include:

• Impotence – the inability to get or maintain an erection sufficient for sexual intercourse
• Ejaculation problems – retrograde (when semen enters the bladder instead of emerging through the penis) and premature ejaculation
• Problems with the testicles – caused by injury, infection or chemotherapy
• Prostatectomy – side effects of the surgical removal of the prostate gland, including infertility, impotence and incontinence
• Certain disorders –multiple sclerosis, diabetes and other disorders can cause erection and ejaculation difficulties
• Antibodies – the man’s immune system makes antibodies that hinder the activity of sperm, such as reducing the sperm’s ability to latch onto his partner’s egg.

Hormonal problems causing infertility in men

The levels of male sex hormones are regulated by a series of glands and their hormones. The pituitary gland in the brain influences hormone production in the testicles under the guidance of the hypothalamus. A relatively uncommon cause of male infertility is the failure to make enough of the hormone gonadotrophin.

Diagnosis of male infertility

Investigating suspected infertility requires tests for both the man and his partner. Diagnosing male infertility may involve:

• Physical examination – including medical history
• Semen analysis – a sample of the man’s semen is investigated in the laboratory and checked for abnormalities and the presence of antibodies
• Blood tests – to assess hormone levels
• Testicular biopsy – a fine needle and microscope are used to check the network of tubes within the testicles to see if they contain any sperm
• Ultrasound scans – to take pictures of the reproductive organs, such as the prostate gland.

Prevention of male infertility

To help improve your fertility, avoid:

• Cigarette smoking
• Alcohol
• Sexually transmitted diseases
• Heat stress from tight-fitting underwear
• Anabolic steroids (taken for body-building or sporting purposes).

Treatment for male infertility

No treatments can improve the quality of a man’s sperm. However, various techniques can increase the odds of conception using the existing sperm quality. 

Many men have sufficient sperm to fertilise their partner's eggs in a test tube, even if they are unable to do so during sexual intercourse. In most cases, the couple can be helped with assisted reproductive technologies (ART). 

The reproductive technologies available to infertile men include:

• Surgery
• Hormone therapy
• Artificial insemination
• In vitro fertilisation (IVF)
• Intra-cytoplasmic sperm injection (ICSI).

Surgery for male infertility

Bloating of veins inside the testes (varicocele) may impair fertility. This condition can be surgically treated. 

The tubes within the male reproductive system that transport sperm may be blocked, perhaps by injury or vasectomy. In some cases, the blockage can be surgically removed and the tubes repaired.

If surgery doesn't work, the man may undergo another surgical procedure called percutaneous epididymal sperm aspiration (PESA). Under local anaesthetic, a slender needle is inserted into the epididymis. Sperm are removed and either used immediately for IVF or frozen for later use.

Hormone therapy for male infertility

The pituitary gland in the brain releases hormones called gonadotropins, which stimulate the testicles to produce sperm. In a small number of cases, male infertility is caused by insufficient levels of these gonadotropins. Taking these hormones as medication may boost sperm production.

Things to remember

• Around 30 per cent of fertility problems originate in the man.
• Male fertility problems include poor quality sperm, low sperm count or blockages in the tubes of the reproductive system.
• Treatment options for poor sperm quality include artificially inseminating the man’s partner with a concentrated sample of the man’s semen.

http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Infertility_in_men

Semen quality

Semen quality is a measure of the ability of semen to accomplish fertilization. Thus, it is a measure of fertility in a man. It is the sperm in the semen that are of importance, and therefore semen quality involves both sperm quantity and quality. Decreased semen quality is a major factor of male infertility.

General decline

There has been evidence for a general decline in sperm counts in Europe and the USA between 1938 and 1990.^[1] While these dates were critiqued, further analysis supported the findings.^[2][3] The reason(s) for the decline are unknown.

Tests

Semen analysis

Main article: Semen analysis

A semen analysis typically measures the number of sperm per milliliter of ejaculate, and analyzes the morphology (shape) and motility (ability to swim forward) of the sperm (the typical ejaculate of a healthy, physically mature young adult male of reproductive age with no fertility-related problems usually contains 300-500 million spermatozoa, though only a couple hundred survive in the acidic environment of the vagina to be candidates for successful fertilization). Also usually measured are the concentration of white blood cells, the level of fructose in the semen, and the volume, pH, and liquefaction time of the ejaculate.^[4][5]

A number of factors may influence the accuracy of semen analysis results, and results for a single man may have a large amount of natural variation over time.^[6] For this reason, a subfertile result must be confirmed with at least two further analyses.^[7]

Hamster zona-free ovum test

Main article: Hamster zona-free ovum test

A man's sperm are mixed with hamster eggs that have had the zona pellucida (outer membranes) removed, and the number of sperm penetrations per egg is measured.^[8] No strong correlation has been found between hamster egg penetration rates and the various semen parameters and the role of the hamster egg penetration test in the investigation of the causes of infertility should be evaluated further.^[9] However, a negative result on the hamster test correlates with a lower probability of the man's partner becoming pregnant.^[10]

Sperm chromatin assay

Chromatin is the complex of DNA and protein that make up chromosomes. If a large percentage of a man's sperm (greater than 30%) have damaged chromatin, his chances of impregnating a partner are significantly reduced, and if he does impregnate his partner, she faces an increased risk of miscarriage. The portion of a man's sperm with damaged chromatin may be determined with a Sperm Chromatin Structure Assay (SCSA).

Antisperm antibodies test

Presence of antisperm antibodies may be responsible for sperm agglutination, reduced sperm motility, abnormal postcoital test. Several tests are presently available including Sperm Immobilization test, Sperm Agglutination tests, Indirect immunofluorescence test, Enzyme-linked immunosorbent assay, Radiolabelled Antiglobulin Assay. One of the most informative and specific tests is Immunobead Rosette Test which can identify different antibody classes involved (IgG, IgA, IgM) and location on the sperm cell (head, body or tail).^[11]

Hemizona test

Hemizona test is a test to evaluate sperm zona-binding capacity. In this test, the two halves of human zona pellucida is incubated with patient's capacitated sperm and control fertile donor's sperm.^[11]

Other tests

• PCR-based detection of the pathogens in the semen of patients with asymptomatic genital infection.^[11]
• Biochemical markers like Creatine kinase, Reactive oxygen species.^[11]

Cryopreservation

When performing cryopreservation of semen, it is the sperm quality after reviving the sample that is of importance, because many sperm cells die in the process.

To be of use in assisted reproductive technology, the sample should after thawing have more than 5 million motile sperm cells per ml with a good grade of mobility. If the grade of mobility is poor, 10 million motile cells per ml is required.^[12]

Home insemination of previously frozen sperm can be accomplished with the use of a cervical cap conception device as a delivery system for the sperm.^[13]

Bad freezers

In 10–20% of all men, the semen doesn't endure cryopreservation.^[12] The cause is unknown. It does not necessarily mean an otherwise bad semen quality.

Sperm washing

When a sperm sample is prepared for intrauterine insemination, it is washed at a facility such as a fertility clinic or a sperm bank. Some sperm does not survive the washing process, as is also the case when freezing the sperm.^[14]

Factors

There are many factors that influence the sperm quality. Exposure to any of the temporary factors can cause up to a three-month delay before sperm quality returns to normal, due to spermiogenesis.^[12]

Age

Further information: Paternal age effect

Although it is possible for men to father children into old age, the genetic quality of sperm, as well as its volume and motility, all typically decrease with age.^[15] In other words, older sperm are less likely to result in a successful pregnancy and, moreover, the cumulative fragmentation of sperm DNA over time^[16] increases the likelihood that a small fraction of men will pass on achondroplasia and transmit multiple genetic and chromosomal defects.^[17] For example, the percentage of sperm with highly damaged DNA, comet extent, DNA break number, and other comet measures has been found to be significantly higher in men aged 36–57 years than in those aged 20–35 years.^[18] Advancing paternal age has been implicated in a number of possible health effects. One particularly well-studied connection is the link between advancing age and autism. For example, one study of 943,664 children less than 10 years old,^[19] found that, with confounding variables controlled, the risk of autism increased with increasing paternal age.^[19] No age related effects on sperm were noted in separate control groups recruited in different geographical locations, indicating that dietary habits, lifestyle or ethnicity could play a part in the quality of sperm.

While advanced age can be a possible factor in sperm motility and health, the sperm of men below 20 years of age has likewise been linked to an increase in birth defects such as neural tube defects, hypospadias, cystic kidney, and Down syndrome.^[20]

Prospective fathers should take up age-related fertility issues with a qualified fertility specialist such as a reproductive endocrinologist.

Masturbation vs intercourse

Semen samples obtained via sexual intercourse contain 70^[21]-120^[22]% more sperm, with sperm having a slightly higher^[23]motility and slightly more normal^[23] morphology, compared with semen samples obtained via masturbation. Sexual intercourse also generates a 25–45%^[23] increase in ejaculate volume, mainly by increased prostate^[24] secretion.

This intercourse advantage is even greater for men with oligospermia.^[23]

However, the single factor or factors for the intercourse advantage have not yet been isolated. It cannot be explained by presence of visual perception of physical attractiveness alone during stimulation,^[23][25] although there may be a slight correlation.^[26] Neither does any substantial fluctuations in sex hormones explain the intercourse advantage.^[24] It is hypothesized that sexual intercourse subdues an inhibition from the central nervous system,^[23] but what, in turn, is the subduing factor is still not completely known.

Heat

Sperm are heat-sensitive, and cannot endure high temperatures. The body has compensatory mechanisms, like thecremaster muscle relaxing and letting the testicle hang further away from the warm body, sweating and a countercurrent exchange of blood cooling inflowing blood. However, despite these compensations, there are activities that should not be performed too often, in order to prevent infertility due to heat;

• sauna sessions^[12]
• bathing for a long time in hot water^[12]
• Long-time tanning bed sessions^[12]
• Placement of a laptop computer over the groin for extended use^[12]

Fever raises the body temperature, which can strike sperm quality. In the same way, sperm quality can be lower in the summer.^[12]

Contrary to widely held beliefs, no evidence supports that wearing constrictive underwear, or "briefs," decreases fertility. Even with an elevation in temperature of 0.8-1° caused by wearing constrictive underwear, no changes in sperm parameters, no decrease in spermatogenesis, and no changes in sperm function are observed ^{[27][dubious – discuss]}

Physical trauma

A blow from outside doesn't affect the sperm quality of already produced sperm cells. Furthermore, the testes are well protected in the scrotum, for example by the tunica vaginalis, making the testes slide away from external pressure rather than being malformed from it; however, a hard enough hit can close or crush the capillaries that supply the sperm producing tissue, resulting in permanent or temporary and partial or total inability to produce sperm in the affected testicle.

Chemicals

There is suspicion that many toxic substances, including several types of medication and hormones, and also constituents of the diet, influence sperm quality.^[12] While a few chemicals with known effects on fertility have been excluded from human consumption, we cannot know if others remain undiscovered. Many products that come into direct contact with spermatozoa lack adequate testing for any adverse effect on semen quality.^[28]

Endocrine disruptors

Endocrine disruptors are chemicals that interfere with the endocrine (hormone) system.

A 2008 report demonstrated evidence of the effects of feminizing chemicals on male development in each class ofvertebrate species as a worldwide phenomenon; these chemical are suspected of reducing the sex ratio and sperm counts in humans.^[29] Ninety-nine percent of over 100,000 recently introduced chemicals are poorly regulated.^[29]

At least three types of synthetic toxins have been found in the semen of student volunteers: polychlorinated biphenyls(PCBs), DDT, and hexachlorobenzene.^[30] DDT and hexachlorobenzene are associated with decreased semen quality, while PCBs are associated with decreased fertility overall.^[28] Leaks of dibromochloropropane (DBCP) have caused sterility in men.^[30] Soldiers that were exposed to dioxins and dioxin-like compounds during the Vietnam war have given rise to children with an increased rate of birth defects.^[30]

Phthalates, a ubiquitous pollutant, may cause decreased sperm production when having been exposed to it during prenatal development.^[28][31]

Other potential xenoestrogens that have been associated with decreased sperm quality in some studies are bisphenol A,nonylphenol and octylphenol.^[28]

Medication

• Depo-Provera, Adjudin, and gossypol are examples of substances used as male contraceptives or in chemical castration. Recent studies have found that THC present in cannabis can confuse the movements of intact sperm, reducing their ability to achieve fertilization.^[32][33]

• Selective serotonin reuptake inhibitors (SSRI) may cause low sperm count.^[34]

• Many antibiotics, e.g. penicillin and tetracycline, suppress sperm production.^[30] It may indirectly reach humans through eating livestock given antibiotics as a growth promoter.

In addition, in vitro studies have observed altered sperm function by the following medications:

• Many psychoactive drugs, including many antidepressants, many antiepileptics (e.g. lithium), and propranolol^[28]
• Opioid analgesics^[28]
• Calcium channel blockers^[28]
• Phosphodiesterase inhibitors (e.g. caffeine, theophylline, pentoxifylline)^[28]
• Statins^[28]
• Calcium chelators (e.g. EDTA)^[28]

Also, numerous products that are intended for exposure to spermatozoa have only a general assumption of safety based on the absence of evidence of actual harm.^[28]

Hormones

• Anabolic steroids use and use of other hormones can reduce sperm quality. Changes in hormone homeostasis affect the spermatogenesis.

The body also has natural variations in hormone concentrations, giving sperm quality natural fluctuations as well.^[12]

Diet

• Drinking over 1 litre of cola a day might decrease sperm quality by up to 30%^[35] (study claims there is correlation, but not causation)

• Soy products decrease sperm quality due to the high content of a type of phytoestrogen called isoflavones.^[36][37]Theoretically, this exposure to high levels of phytoestrogen in men may alter the hypothalamic-pituitary-gonadal axis. A few studies on animals have shown that such a hormonal effect may be significant and decrease fertility.^[38] On the other hand, most studies have shown that isoflavone supplements have little to no effect on sperm concentration, count, or mobility, and cause no changes in testicular or ejaculate volume.^[39][40]

• A review in 2010 concluded that there is little evidence for a relationship with semen parameters and increased BMI.^[41]

• Folate (vitamin B₉) may protect sperm cells from aneuploidy.^[42]

• Gossypol has been associated with reduced sperm production. It is present in crude cottonseed oil, and potentially the organ meats from animals poisoned with it^[43])

Other chemicals

Environmental mutagens that are associated with decreased semen quality include the following:

• Plutonium, widely spread from nuclear weapon tests, accumulates in the testes, where it disrupts zinc metabolism, in turn causing genetic damage.^[30]
• Ethylene oxide, a chemical sterilizer, is associated with decreased semen quality.^[28]

Other environmental agents associated with decreased semen quality include:

• Cadmium, causing damage to Sertoli cells, thereby impeding spermatogenesis.^[28]
• Lead, causing reduced spermatogenesis and abnormal spermatozoa.^[28]
• Mercury, being highly damaging to spermatogenesis.^[28]
• Many pesticides, causing decreased semen quality as well as sperm chromosome anomalies.^[28]
• Polybrominated diphenyl ethers (PBDEs).^[28]
• Many solvents, such as benzene, toluene, xylene, styrene, 1-bromopropane, 2-bromopropane, perchloroethylene,trichloroethylene.^[28]

Last ejaculation

How long the man has abstained prior to providing a semen sample correlates with the results of semen analysis and also with success rates in assisted reproductive technology (ART).

Both a too short period of time since last ejaculation and a too long one reduces semen quality.

A period of time of less than one day reduces sperm count by at least 20%.^[44]

Longer periods of abstinence correlate with poorer results – one study found that couples where the man had abstained for more than 10 days before an intrauterine insemination (IUI) had only a 3% pregnancy rate. An abstinence period of only 1 or 2 days produce the highest pregnancy rates per IUI cycle compared with longer intervals of ejaculatory abstinence.^[45]This increase in pregnancy rate occurs despite a lower value of total motile spermatozoa.^[45] Daily sexual activity increases sperm quality in men minimizing DNA damage in the sperm -because it is speculated to result in less storage time where damage may accumulate.^[46]

Environment

For semen that has been ejaculated, the quality deteriorates with time. However, this lifetime can be shortened or prolonged, depending on the environment.

Outside body

Sperm outside of the body generally has a life expectancy which is considered to depend on pH, temperature, presence of air and other factors, and is unpredictable but smaller than the life expectancy inside the human body.^{[citation needed]} For instance, sperm donors who collect the sample outside the cinic are advised to have handed in the sample no more than one hour from collection, and to keep it, if not at body temperature, then at least at room temperature.^[47]

In a non-harmful environment outside the body, such as in a sterile glass container^[23] the number of motile sperm decreases with approximately 5-10%^[23] per hour. In contrast, in a latex condom, the quality decreases with 60-80%^[23] per hour, rendering the sample unusable in not too long time.

In female

The environment in the uterus and fallopian tubes are advantageous. A pregnancy resulting from sperm life of eight days has been documented.^[48][49][50]

Home or in clinic

The sperm quality is better if the sample is collected at home than in the clinics.^[51] Collecting the sperm at home gives a higher sperm concentration, sperm count and motility particularly if the sperm is collected via sexual intercourse.^[51]

Mobile phones

Having a mobile phone in talk mode in the pocket, like when using handsfree, has been suggested to be a risk if often used in the long-term.^[52]

In an in vitro study, sperm samples (in a petri dish) exposed to radio frequency electromagnetic waves (as in mobile phones) showed significantly decreased sperm motility and viability, increased ROS level, and decreased ROS-TAC score.^[53]

Others

Tobacco smoking lowers the sperm quality,^[30] perhaps by decreased ability to attach to hyaluronan on the egg cell.^[54]However, the influence is probably minor.^[12] Smoking cannabis can decrease sperm quantity.^[30]

Long-term stress is also suggested.^[12]

Higher levels of intelligence are also correlated with higher levels of sperm quality in three key indicators: sperm concentration, sperm count and sperm motility. Men who scored high on a battery of intelligence tests tended to have higher counts of healthy sperm, while low scorers tended to have fewer and more sickly sperm. It is conceivable that intelligence might tip off a man's overall health to women looking for a mate with healthy genes, explained University of New Mexico evolutionary psychologist Geoffrey Miller at a talk at Harvard University. "Though the connections between brains and sperm were 'not awesome, they're there and highly significant,' Miller said. All things held equal, good sperm and good brains go together."^[55][56]

Regarding diet, malnutrition or an unhealthy diet can lead to e.g. Zinc deficiency, lowering sperm quality.

Sperm quality is better in the afternoon than in the morning.^[57] Adrenaline-levels are higher during awakening (~06.00 to noon),^[58] which may contribute similarly to general stress.

Lack of exercise, as well as excessive exercise, are minor factors. In professional sports, semen quality parameters tend to decrease as training requirements increase. The effect differs substantially between different professional sport types. For example, water polo appears substantially less harmful to semen quality than triathlon.^[59]

A longer duration of sexual stimulation before ejaculation slightly increases sperm quality.^[60]

During the three decades leading up to the early 1990s, several studies suggested a population-wide decline in the quality of semen over the past 50 years. Definitive evidence for decreasing semen quality was lacking until a 1996 study published in the New England Journal of Medicine concluded that from 1973 to 1992 "each successive calendar year of birth accounted for 2.6 percent of the yearly decline in the sperm concentration, for 0.3 percent of the yearly declines in the percentages of motile, and 0.7 percent of the yearly declines in the percentages of normal spermatozoa (all P<0.001)".^[61]

Males carrying Robertsonian translocations in their chromosomes have significantly higher degree of sperm cell apoptosisand lower concentration. Sperm cells also have decreased forward motility, but normal morphology.^[62]

Testicular cancer, Leydig cell tumours and Sertoli cell tumours are also associated with reduced sperm count and quality.^[63]

http://en.wikipedia.org/wiki/Semen_quality

Corpus luteum

The corpus luteum (Latin for "yellow body"; plural corpora lutea) is a temporary endocrine structure in female mammals that is involved in the production of relatively high levels of progesterone and moderate levels of estradiol and inhibin A. It is colored as a result of concentratingcarotenoids (including lutein) from the diet and secretes a moderate amount of estrogen to inhibit further release of gonadotropin-releasing hormone (GnRH) and thus secretion of luteinising hormone (LH) andfollicle-stimulating hormone (FSH). A new corpus luteum develops with each menstrual cycle.

Development and structure

The corpus luteum develops from an ovarian follicle during the luteal phase of the menstrual cycle or oestrous cycle, following the release of a secondary oocyte from the follicle during ovulation. The follicle first forms a corpus hemorrhagicum before it becomes a corpus luteum, but the term refers to the visible collection of blood left after rupture of the follicle that secretes progesterone. While the oocyte (later the zygote if fertilization occurs) traverses the Fallopian tube into the uterus, the corpus luteum remains in the ovary.

The corpus luteum is typically very large relative to the size of the ovary; in humans, the size of the structure ranges from under 2 cm to 5 cm in diameter.^[1][2]

Its cells develop from the follicular cells surrounding the ovarian follicle.^[3] The follicular theca cells luteinize into small luteal cells (thecal-lutein cells) and follicular granulosa cells luteinize into large luteal cells (granulosal-lutein cells) forming the corpus luteum. Progesterone is synthesized from cholesterol by both the large and small luteal cells upon luteal maturation. Cholesterol-LDL complexes bind to receptors on the plasma membrane of luteal cells and are internalized. Cholesterol is released and stored within the cell as cholesterol ester. LDL is recycled for further cholesterol transport. Large luteal cells produce more progesterone due to uninhibited/basal levels of protein kinase A (PKA) activity within the cell. Small luteal cells have LH receptors that regulate PKA activity within the cell. PKA actively phosphorylates steroidogenic acute regulatory protein (StAR) and translocator protein to transport cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane.^[4]

The development of the corpus luteum is accompanied by an increase in the level of the steroidogenic enzyme P450sccthat converts cholesterol to pregnenolone in the mitochondria.^[5] Pregnenolone is then converted to progesterone that is secreted out of the cell and into the blood stream. During the bovine estrous cycle, plasma levels of progesterone increase in parallel to the levels of P450scc and its electron donor adrenodoxin, indicating that progesterone secretion is a result of enhanced expression of P450scc in the corpus luteum.^[5]

The mitochondrial P450 system electron transport chain including adrenodoxin reductase and adrenodoxin has been shown to leak electrons leading to the formation of superoxide radical.^[6][7] Apparently to cope with the radicals produced by this system and by enhanced mitochondrial metabolism, the levels of antioxidant enzymes catalase and superoxide dismutase also increase in parallel with the enhanced steroidogenesis in the corpus luteum.^[5]

Like the previous theca cells, the theca lutein cells lack the aromatase enzyme that is necessary to produce estrogen, so they can only perform steroidogenesis until formation of androgens.^[9] The granulosa lutein cells do have aromatase, and use it to produce estrogens, using the androgens previously synthesized by the theca lutein cells, as the granulosa lutein cells in themselves do not have the 17α-hydroxylase or 17,20 lyase to produce androgens.^[9]

Once the corpus luteum regresses the remnant is known as corpus albicans.^[10]

Function

The corpus luteum is essential for establishing and maintaining pregnancy in females. The corpus luteum secretes progesterone, which is a steroid hormoneresponsible for the decidualization of the endometrium (its development) and maintenance, respectively.

When egg is not fertilized

If the egg is not fertilized, the corpus luteum stops secreting progesterone and decays (after approximately 10 days in humans). It then degenerates into a corpus albicans, which is a mass of fibrous scartissue.

The uterine lining sloughs off without progesterone and is expelled through the vagina (in mammals that go through amenstrual cycle). In an estrous cycle, the lining degenerates back to normal size.

When egg is fertilized

If the egg is fertilized and implantation occurs, the syncytiotrophoblast (derived fromtrophoblast) cells of the blastocyst secrete the hormone human chorionic gonadotropin(hCG, or a similar hormone in other species) by day 9 post-fertilization.

Human chorionic gonadotropin signals the corpus luteum to continue progesterone secretion, thereby maintaining the thick lining (endometrium) of the uterus and providing an area rich in blood vessels in which the zygote(s) can develop. From this point on, the corpus luteum is called the corpus luteum graviditatis.

The introduction of prostaglandins at this point causes the degeneration of the corpus luteum and the abortion of the fetus. However, in placental animals such as humans, theplacenta eventually takes over progesterone production and the corpus luteum degrades into a corpus albicans without embryo/fetus loss.

Luteal support refers to the administration of medication (generally progestins) for the purpose of increasing the success ofimplantation and early embryogenesis, thereby complementing the function of the corpus luteum.

Content of carotenoids

The yellow color and name of the corpus luteum, like that of the macula lutea of the retina, is due to its concentration of certain carotenoids, especially lutein. In 1968, a report indicated that beta-carotene was synthesized in laboratory conditions in slices of corpus luteum from cows. However, attempts have been made to replicate these findings, but have not succeeded. The idea is not presently accepted by the scientific community.^[11] Rather, the corpus luteum concentrates carotenoids from the diet of the mammal.

http://en.wikipedia.org/wiki/Corpus_luteum

Ovarian cyst

An ovarian cyst is any collection of fluid, surrounded by a very thin wall, within an ovary.^[1] Any ovarian follicle that is larger than about two centimeters is termed an ovarian cyst. Such cysts range in size from as small as a pea to larger than an orange.

The vast majority of ovarian cysts are harmless (benign), most are functional cysts.^[1][2]

Ovarian cysts occur in women of all ages including neonatal period and infancy. They are most prevalent during infancy, adolescence and during the childbearing years. With ultrasonography ovarian cysts can be demonstrated in nearly all premenopausal and approximately 18% postmenopausal women.^[2]

Some ovarian cysts cause problems, such as bleeding and pain or may raise concerns of malignancy. Surgery may be required to remove cysts larger than 5 centimeters in diameter.

Classification

Ovarian cysts may be classified according to whether they are a variant of the normal menstrual cycle, called a functional cyst, or not.^[3]

Ovarian cysts are considered large when they are over 5 cm and giant when they are over 15 cm. In children ovarian cysts reaching above the level of the umbilicus are considered as giant.

Functional

Functional cysts form as a normal part of the menstrual cycle. There are several types of cysts:

·         Follicular cyst, the most common type of ovarian cyst. In menstruating women, a follicle containing the ovum(unfertilized egg) will rupture during ovulation. If this does not occur, a follicular cyst of more than 2.5 cm diameter may result.^[3]

·         Corpus luteum cysts appear after ovulation. The corpus luteum is the remnant of the follicle after the ovum has moved to the fallopian tubes. This normally degrades within 5–9 days. A corpus lutem that is more than 3 cm is defined as cystic.^[3]

·         Theca lutein cysts occur within the thecal layer of cells surrounding developing oocytes. Under the influence of excessive hCG, thecal cells may proliferate and become cystic. This is usually on both ovaries.^[3]

Non-functional

Non-functional cysts may include the following:

·         An ovary with many cysts, which may be found in normal women, or within the setting of polycystic ovary syndrome.

·         Cysts caused by endometriosis, known as chocolate cysts.

·         Hemorrhagic ovarian cyst

·         Dermoid cyst

·         Ovarian serous cystadenoma

·         Ovarian mucinous cystadenoma

·         Paraovarian cyst

·         Cystic adenofibroma

·         Borderline tumoral cysts

Juvenile

Benign ovarian cysts are common in unsymptomatic premenarchal girls and found in approximately 68% of ovaries of girls 2-12 years old and in 84% of ovaries of girls 0-2 years old. Most of them are smaller than 9 mm while about 10-20% are larger macrocysts. While the smaller cysts mostly disappear within 6 months the larger ones appear to be more persistent.^[4][5]

In juvenile hypothyroidism multicystic ovaries are present in about 75% of cases while large ovarian cysts and elevated ovarian tumor markes are one of the symptoms of the Van Wyk and Grumbach syndrome.^[6]

The CA-125 marker in children and adolescents can be frequently elevated even in absence of malignancy and conservative management should be considered.

Signs and symptoms[edit]

Some or all of the following symptoms may be present, though it is possible not to experience any symptoms:^[3]

·         Abdominal pain. Dull aching pain within the abdomen or pelvis, especially on intercourse.

·         Uterine bleeding. Pain during or shortly after beginning or end of menstrual period; irregular periods, or abnormal uterine bleeding or spotting.

·         Fullness, heaviness, pressure, swelling, or bloating in the abdomen.

·         When a cyst ruptures from the ovary, there may be sudden and sharp pain in the lower abdomen on one side.

·         Change in frequency or ease of urination (such as inability to fully empty the bladder), or difficulty with bowel movements due to pressure on adjacent pelvic anatomy.

·         Constitutional symptoms such as fatigue, headaches

·         Nausea or vomiting

·         Weight gain

Other symptoms may depend on the cause of the cysts:^[3]

·         Symptoms that may occur if the cause of the cysts is polycystic ovarian syndrome may include increased facial hair orbody hair, acne, obesity and infertility.

·         If the cause is endometriosis, then periods may be heavy, and intercourse painful.

Diagnosis

An Axial CT demonstrating a large hemorrhagic ovarian cyst. The cyst is delineated by the yellow bars with blood seen anteriorly.

Ovarian cysts are usually diagnosed by either ultrasound or CT scan, with additional endocrinological tests.

Follow-up imaging for women of reproductive age with small simple or hemorrhagic cyst is generally not required.^[7]

There are several systems for scoring of the risk of an ovarian cyst of being anovarian cancer, including RMI (risk of malignancy index), LR2 and SR (simple rules). Sensitivities and specificities of these systems are given in tables below:^[8]

Scoring systems	Premenopausal		Postmenopausal
	Sensitivity	Specificity	Sensitivity	Specificity
RMI I	44%	95%	79%	90%
LR2	85%	91%	94%	70%
SR	93%	83%	93%	76%

Risk of malignancy index

A widely recognised method of estimating the risk of malignant ovarian cancer based on initial workup is the risk of malignancy index (RMI).^[9]

It is recommended that women with an RMI score over 200 should be referred to a centre with experience in ovarian cancer surgery.^[10]

The RMI is calculated as follows:^[10]

RMI = ultrasound score x menopausal score x CA-125 level in U/ml.

There are two methods to determine the ultrasound score and menopausal score, with the resultant RMI being called RMI 1 and RMI 2, respectively, depending on what method is used:^[10]

Feature	RMI 1	RMI 2
Ultrasound abnormalities: ·         multilocular cyst ·         solid areas ·         bilateral lesions ·         ascites ·         intra-abdominal metastases	·         0 = no abnormality ·         1 = one abnormality ·         3 = two or more abnormalities	·         0 = none ·         1 = one abnormality ·         4 = two or more abnormalities
Menopausal score	·         1 = premenopausal ·         3 = postmenopausal	·         1 = premenopausal ·         4 = postmenopausal
CA-125	Quantity in U/ml	Quantity in U/ml

An RMI 2 of over 200 has been estimated to have a sensitivity of 74 to 80%, a specificity of 89 to 92% and a positive predictive value of around 80% of ovarian cancer.^[10] RMI 2 is regarded as more sensitive than RMI 1.^[10]

Treatment

Cysts associated with hypothyroidism or other endocrine problems are treated by treating the underlying condition.

About 95% of ovarian cysts are benign, not cancerous.^[11]

Functional cysts and hemorrhagic ovarian cysts usually resolve spontaneously.^[12] However the bigger an ovarian cyst is, the less likely it is to disappear on its own.^[13] Treatment may be required if cysts persist over several months, grow or cause increasing pain.^[14] Treatment for cysts depends on the size of the cyst and symptoms.

Pain associated with ovarian cysts may be treated in several ways:

·        Pain relievers, including acetaminophen/paracetamol (Tylenol or Panadol), nonsteroidal anti-inflammatory drugs such as ibuprofen (Motrin, Advil), or narcotic pain medicine (by prescription) may help reduce pelvic pain.^[15] NSAIDs usually work best when taken at the first signs of the pain.

·        A warm bath, or heating pad, or hot water bottle applied to the lower abdomen near the ovaries can relax tense muscles and relieve cramping, lessen discomfort, and stimulate circulation and healing in the ovaries.^[16]

·        Combined methods of hormonal contraception such as the combined oral contraceptive pill – the hormones in the pills may regulate the menstrual cycle, and prevent the formation of follicles that can turn into cysts.(American College of Obstetricians and Gynecologists, 1999c; Mayo Clinic, 2002e)^[15] However, a Cochrane review in 2011 concluded oral contraceptives are of no benefit in treating already present functional cysts.^[17]

Also, limiting strenuous activity may reduce the risk of cyst rupture or torsion.

Cysts that persist beyond two or three menstrual cycles, or occur in post-menopausal women, may indicate more serious disease and should be investigated through ultrasonography and laparoscopy, especially in cases where family members have had ovarian cancer. Such cysts may require surgical biopsy. Additionally, a blood test may be taken before surgery to check for elevated CA-125, a tumour marker, which is often found in increased levels in ovarian cancer, although it can also be elevated by other conditions resulting in a large number of false positives.^[18]

For more serious cases where cysts are large and persisting, doctors may suggest surgery. This may involve removing the cyst, or one or both ovaries.^[19] Features that may indicate the need for surgery include:^[20]

·        Persistent complex ovarian cysts

·        Persistent cysts that are causing symptoms

·        Complex ovarian cysts larger than 5 cm

·        Simple ovarian cysts larger 10 centimeters or larger than 5 cm in postmenopausal patients

·        Women who are menopausal or perimenopausal

Complications

Ovarian cyst rupture

The rupture of an ovarian cyst is usually self-limiting, and only requires expectant management and analgesics. The main symptom is abdominal pain, but can also be asymptomatic. The pain may last from a few days to several weeks.^[21]Rupture of large ovarian cysts can cause massive hemoperitoneum and in some cases shock and serious complications.

Ovarian torsion

Ovarian cysts increase the risk for ovarian torsion, cysts larger than 4 cm are associated with approximately 17% risk. The torsion can cause obstruction of blood flow and lead to infarction.^[2]

http://en.wikipedia.org/wiki/Ovarian_cyst

Uterine fibroid

A uterine fibroid (also known as uterine leiomyoma,^[1] myoma,fibromyoma, fibroleiomyoma) is a leiomyoma (benign tumor from smooth muscle tissue) that originates from the smooth muscle layer (myometrium) of the uterus. Fibroids are often multiple and if the uterus contains too many leiomyomata to count, it is referred to as diffuse uterine leiomyomatosis. The malignant version of a fibroid is extremely uncommon and termed aleiomyosarcoma.

Fibroids are the most common benign tumors in females and typically found during the middle and later reproductive years. While most fibroids are asymptomatic, they can grow and cause heavy and painful menstruation,painful sexual intercourse, urinary frequency and urgency. Some fibroids may interfere with pregnancy although this appears to be very rare.^[2]

In the United States, symptoms caused by uterine fibroids are a very frequent indication for surgical removal of the uterus.^[3]

Signs and symptoms

Fibroids, particularly when small, may be entirely asymptomatic. Symptoms depend on the location of the lesion and its size. Important symptoms include abnormal gynecologic hemorrhage, heavy or painful periods, abdominal discomfort or bloating, painful defecation, back ache, urinary frequency or retention, and in some cases, infertility.^[4] There may also be pain during intercourse, depending on the location of the fibroid. During pregnancy they may also be the cause ofmiscarriage, bleeding, premature labor, or interference with the position of the fetus.

While fibroids are common, they are not a typical cause for infertility accounting for about 3% of reasons why a woman may not be able to have a child.^[5] The majority of women with uterine fibroids will have normal pregnancy outcomes.^[6][7] In cases of intercurrent uterine fibroids in infertility, a fibroid is typically located in a submucosal position and it is thought that this location may interfere with the function of the lining and the ability of the embryo to implant.^[5] Also larger fibroids may distort or block the fallopian tubes.

Cause

Genetics

An association with fatty acid synthase has been reported.^[8]

 

Familial leiomyomata

For more details on this topic, see Hereditary leiomyomatosis and renal cell cancer.

A syndrome (Reed’s syndrome) that causes uterine leiomyomata along with cutaneous leiomyomata and renal cell cancerhas been reported.^[9][10][11] This is associated with a mutation in the gene that produces the enzyme fumarate hydratase, located on the long arm of chromosome 1 (1q42.3-43). Inheritance is autosomal dominant.

Pathophysiology

Leiomyomata grossly appear as round, well circumscribed (but not encapsulated), solid nodules that are white or tan, and show whorled appearance on histological section. The size varies, from microscopic to lesions of considerable size. Typically lesions the size of a grapefruit or bigger are felt by the patient herself through the abdominal wall..

Microscopically, tumor cells resemble normal cells (elongated, spindle-shaped, with a cigar-shaped nucleus) and form bundles with different directions (whorled). These cells are uniform in size and shape, with scarce mitoses. There are three benign variants: bizarre (atypical); cellular; and mitotically active.

The appearance of prominent nucleoli with perinucleolar halos should alert the pathologist to investigate the possibility of the extremely rare hereditary leiomyomatosis and renal cell cancer syndrome.^[12]

Location and classification

Growth and location are the main factors that determine if a fibroid leads to symptoms and problems.^[3] A small lesion can be symptomatic if located within the uterine cavity while a large lesion on the outside of the uterus may go unnoticed. Different locations are classified as follows:

·         Intramural fibroids are located within the wall of the uterus and are the most common type; unless large, they may be asymptomatic. Intramural fibroids begin as small nodules in the muscular wall of the uterus. With time, intramural fibroids may expand inwards, causing distortion and elongation of the uterine cavity.

·         Subserosal fibroids are located underneath the mucosal (peritoneal) surface of the uterus and can become very large. They can also grow out in a papillary manner to become pedunculated fibroids. These pedunculated growths can actually detach from the uterus to become a parasitic leiomyoma.

·         Submucosal fibroids are located in the muscle beneath the endometrium of the uterus and distort the uterine cavity; even small lesions in this location may lead to bleeding and infertility. A pedunculated lesion within the cavity is termed an intracavitary fibroid and can be passed through the cervix.

·         Cervical fibroids are located in the wall of the cervix (neck of the uterus). Rarely, fibroids are found in the supporting structures (round ligament, broad ligament, or uterosacral ligament) of the uterus that also contain smooth muscle tissue.

Fibroids may be single or multiple. Most fibroids start in the muscular wall of the uterus. With further growth, some lesions may develop towards the outside of the uterus or towards the internal cavity. Secondary changes that may develop within fibroids are hemorrhage, necrosis, calcification, and cystic changes.

Extrauterine fibroids of uterine origin, metastatic fibroids[edit]

Fibroids of uterine origin located in other parts of the body, sometimes also called parasitic myomas have been historically extremely rare, but are now diagnosed with increasing frequency. They may be related or identical to metastasizingleiomyoma.

They are in most cases still hormone dependent but may cause life-threatening complications when they appear in distant organs. Some sources suggest that a substantial share of the cases may be late complications of surgeries such as myomectomy or hysterectomy. Particularly laparoscopic myomectomy using a morcellator has been associated with a substantially increased risk of this complication.^{[13][14][15][16][17]}

There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can be dangerous depending on their location.^[18]

·         In leiomyoma with vascular invasion, an ordinary-appearing fibroid invades into a vessel but there is no risk of recurrence.

·         In Intravenous leiomyomatosis, leiomyomata grow in veins with uterine fibroids as their source. Cardiac involvement can be fatal.

·         In benign metastasizing leiomyoma, leiomyomata grow in more distant sites such as the lungs and lymph nodes. The source is not entirely clear. Pulmonary involvement can be fatal.

·         In disseminated intraperitoneal leiomyomatosis, leiomyomata grow diffusely on the peritoneal and omental surfaces, with uterine fibroids as their source. This can simulate a malignant tumor but behaves benignly.

 

Pathogenesis

Fibroids are monoclonal tumors and approximately 40 to 50% show karyotypicallydetectable chromosomal abnormalities. When multiple fibroids are present they frequently have unrelated genetic defects. Specific mutations of the MED12 protein have been noted in 70 percent of fibroids.^[19]

Exact aetiology is not clearly understood, but the current working hypothesis is that genetic predispositions, prenatal hormone exposure and the effects of hormones, growth factors and xenoestrogens cause fibroid growth. Known risk factors are African descent, nulliparity, obesity, polycystic ovary syndrome, diabetes, andhypertension.^[20]

Fibroid growth is strongly dependent on estrogen and progesterone. Although both estrogen and progesterone are usually regarded as growth-promoting they will also cause growth restriction in some circumstances. Paradoxically, fibroids rarely grow during pregnancy despite very high steroid hormone levels and pregnancy appears to exert a certain protective effect.^[2] This protective effect might be partially mediated by an interaction between estrogen and the oxytocin receptor.^[21]

It is believed that estrogen and progesterone have a mitogenic effect on leiomyoma cells and also act by influencing (directly and indirectly) a large number of growth factors, cytokines and apoptotic factors as well as other hormones. Furthermore, the actions of estrogen and progesterone are modulated by the cross-talk between estrogen, progesterone and prolactin signalling which controls the expression of the respective nuclear receptors. It is believed that estrogen promotes growth by up-regulating IGF-1, EGFR, TGF-beta1, TGF-beta3 and PDGF, and promotes aberrant survival of leiomyoma cells by down-regulating p53, increasing expression of the anti-apoptotic factor PCP4 and antagonizing PPAR-gamma signalling. Progesterone is thought to promote the growth of leiomyoma through up-regulating EGF, TGF-beta1 and TGF-beta3, and promotes survival through up-regulating Bcl-2 expression and down-regulating TNF-alpha. Progesterone is believed to counteract growth by downregulating IGF-1.^[22][23][24] Expression of transforming growth interacting factor (TGIF) is increased in leiomyoma compared with myometrium.^[25] TGIF is a potential repressor of TGF-βpathways in myometrial cells.^[25]

Whereas in premenopausal fibroids the ER-beta, ER-alpha and progesterone receptors are found overexpressed, in the rare postmenopausal fibroids only ER-beta was found significantly overexpressed.^[26] Most studies found that polymorphisms in ER and PR gene encodings are not correlated with incidence of fibroids in Caucasian populations^[27][28]however a special ER-alpha genotype was found correlated with incidence and size of fibroids. The higher prevalence of this genotype in black women may also explain the high incidence of fibroids in this group.^[29]

Several lines of evidence as well as plausible epidemiological data show possible connections of low Vitamin D3 levels with the growth of uterine fibroids.^[30][31] Experiments in rats show that Vitamin D3 supplementation can in some circumstances shrink fibroids.^[32]

Uterine leiomyoma was more sensitive than normal myometrium to PPAR-gamma receptor activation resulting in reduced survival and apoptosis of leiomyoma cells. The mechanism is thought to involve negative cross-talk between ER and PPAR signaling pathways. Several PPAR-gamma ligands were considered as potential treatment.^[33] PPAR-gamma agonists may also counteract leiomyoma growth by several other mechanisms of action such as TGF-beta3 expression inhibition.^[34]

Hypertension is significantly correlated with fibroids. Although a causal relationships is not at all clear the hypothesis has been formulated that atherosclerotic injury to uterine blood vessels and the resulting inflammatory state may play a role. Furthermore endocrine factors related to blood pressure such as angiotensin II are suspected to cause fibroid proliferation via angiotensin II type 1 receptor.^[35][36]

Aromatase and 17beta-hydroxysteroid dehydrogenase are aberrantly expressed in fibroids, indicating that fibroids can convert circulating androstenedione into estradiol.^[37] Similar mechanism of action has been elucidated in endometriosisand other endometrial diseases.^[38] Aromatase inhibotors are currently considered for treatment, at certain doses they would completely inhibit estrogen production in the fibroid while not largely affecting ovarian production of estrogen (and thus systemic levels of it). Aromatase overexpression is particularly pronounced in Afro-American women.^[39]

Genetic and hereditary causes are being considered and several epidemiologic findings indicate considerable genetic influence especially for early onset cases. First degree relatives have a 2.5-fold risk, and nearly 6-fold risk when considering early onset cases. Monozygotic twins have double concordance rate for hysterectomy compared to dizygotic twins.^[40]

Expansion of uterine fibroids is by a slow rate of cell proliferation combined with the production of copious amounts ofextracellular matrix.^[41] Recent studies suggest that this production may represent an abnormal response to ischemic and mechanical tissue stress.^[42] Several factors indicate significant involvement of extracellular signaling pathways such asERK1 and ERK2, which in fibroids are prominently influenced by hormones.^[43] Paradoxically and unlike most other conditions involving significant fibrosis the CYR61 gene has been found downregulated in fibroids.^[44]

Cyr61 is also known for its role as tumor suppressing factor and in angiogenesis. Hence fibroids are one of the very few tumors with reduced vascular density.^[44]

A small population of the cells in an uterine fibroid have properties of stem cells or progenitor cells, and contribute significantly to ovarian steroid-dependent growth of fibroids. These stem-progenitor cells are deficient in estrogen receptor α and progesterone receptor and instead rely on substantially higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone actions via paracrine signalling.^[41]

Diagnosis

While a bimanual examination typically can identify the presence of larger fibroids, gynecologic ultrasonography(ultrasound) has evolved as the standard tool to evaluate the uterus for fibroids. Sonography will depict the fibroids as focal masses with a heterogeneous texture, which usually cause shadowing of the ultrasound beam. The location can be determined and dimensions of the lesion measured. Also magnetic resonance imaging (MRI) can be used to define the depiction of the size and location of the fibroids within the uterus.

Imaging modalities cannot clearly distinguish between the benign uterine leiomyoma and the malignant uterine leiomyosarcoma, however, the latter is quite rare. Fast growth or unexpected growth, such as enlargement of a lesion after menopause, raise the level of suspicion that the lesion might be a sarcoma. Also, with advanced malignant lesions there may be evidence of local invasion. A more recent study has suggested that diagnostic capabilities using MRI have improved the ability to detect sarcomatous lesions.^[45] Biopsy is rarely performed and if performed, is rarely diagnostic. Should there be an uncertain diagnosis after ultrasounds and MRI imaging, surgery is generally indicated.

Other imaging techniques that may be helpful specifically in the evaluation of lesions that affect the uterine cavity arehysterosalpingography or sonohysterography.

Coexisting disorders

Fibroids that lead to heavy vaginal bleeding lead to anemia and iron deficiency. Due to pressure effects gastrointestinal problems such as constipation and bloatedness are possible. Compression of the ureter may lead to hydronephrosis. Fibroids may also present alongside endometriosis, which itself may cause infertility. Adenomyosis may be mistaken for or coexist with fibroids.

In very rare cases, malignant (cancerous) growths, leiomyosarcoma, of the myometrium can develop.^[46] In extremely rare cases uterine fibroids may present as part or early symptom of the hereditary leiomyomatosis and renal cell cancersyndrome.

Treatment

Most fibroids do not require treatment unless they are causing symptoms. After menopause fibroids shrink and it is unusual for them to cause problems. In those who have symptoms uterine artery embolization and surgical options have similar outcomes with respect to satisfaction.^[47]

Symptomatic uterine fibroids can be treated by:

·         medication to control symptoms

·         medication aimed at shrinking tumours

·         ultrasound fibroid destruction

·         myomectomy or radio frequency ablation

·         hysterectomy

·         uterine artery embolization

Medication

A number of medications may be used to control symptoms. NSAIDs can be used to reduce painful menses. Oral contraceptive pills are prescribed to reduce uterine bleeding and cramps.^[5] Anemia may have to be treated with iron supplementation. Vitamin D3 supplementation can be tried.^[30][31][32]

Levonorgestrel intrauterine devices are highly effective in limiting menstrual blood flow and improving other symptoms. Side effects are typically very moderate because the levonorgestrel (a progestin) is released in low concentration locally. There is now substantial evidence that Levongestrel-IUDs provide good symptomatic relief for women with fibroids.^[48] While most Levongestrel-IUD studies concentrated on treatment of women without fibroids a few reported very good results specifically for women with fibroids including a substantial regression of fibroids.^[49][50][51]

Dostinex in a moderate and well tolerated dosis has been shown in 2 studies to shrink fibroids effectively. Mechanism of action is unclear.^[50][52]

Ulipristal acetate is a synthetic selective progesterone receptor modulator which has been tested in several radomized trials with good results for the treatment of fibroids.^[53] [54] Similar to other selective progesterone receptor modulators and antagonists benign histologic endometrial changes were reported and long term safety outside of clinical studies has not been established yet.^[53][55][56]

Danazol is an effective treatment to shrink fibroids and control symptoms. Its use is limited by unpleasant side effects. Mechanism of action is thought to be antiestrogenic effects. Recent experience indicates that safety and side effect profile can be improved by more cautious dosing.^[50]

Gonadotropin-releasing hormone analogs cause temporary regression of fibroids by decreasing estrogen levels. Because of the limitations and side effects of this medication it is rarely recommended other than for preoperative use to shrink the size of the fibroids and uterus before surgery. It is typically used for a maximum of 6 months or less because after longer use they could cause osteoporosis and other typically postmenopausal complications. The main side effects are transient postmenopausal symptoms. In many cases the fibroids will regrow after cessation of treatment, however significant benefits may persist for much longer in some cases. Several variations are possible, such as GnRH agonists with add-back regimens intended to decrease the adverse effects of estrogen deficiency. Several add-back regimes are possible, tibolone,raloxifene, progestogens alone, estrogen alone, and combined estrogens and progestogens.^[50]

Ulipristal acetate is a synthetic selective progesterone receptor modulator which has been tested in small radomized trials with good results for the treatment of fibroids.^[53] Similar to other selective progesterone receptor modulators and antagonists benign histologic endometrial changes were reported and long term safety outside of clinical studies has not been established yet.^[53][57][55]

Progesterone antagonists such as Mifepristone have been tested, there is evidence that it relieves some symptoms and improves quality of life but because of adverse histological changes that have been observed in several trials it can not be currently recommended outside of research setting.^[58][59][60] Fibroid growth has recurred after antiprogestin treatment was stopped.^[41] Selective progesterone receptor modulators, such as Progenta, have been under investigation.

The selective progesterone receptor modulator Asoprisnil is currently tested with very promising results as a possible use as a treatment for fibroids - the hope is that it will provide the advantages of progesterone antangonitst without their adverse effects.^[50]

The long term safety of progesterone antagonists as well as selective progesterone receptor modulators has yet to be established.^[61]

Aromatase inhibitors have been used experimentally to reduce fibroids. The effect is believed to be due partially by lowering systemic estrogen levels and partially by inhibiting locally overexpressed aromatase in fibroids.^[50] However, fibroid growth has recurred after treatment was stopped.^[41] Experience from experimental aromatase inhibitor treatment of endometriosisindicates that aromatase inhibitors might be particularly useful in combination with a progestogenic ovulation inhibitor.

Uterine artery embolization

Uterine artery embolization (UAE): is a noninvasive, endovascular procedure effectively treating symptomatic fibroids. Usinginterventional radiology techniques, the interventional radiologist occludes both uterine arteries, thus reducing blood supply to the fibroid.^[62] This intervention is not usually recommended when fertility should be preserved although subsequent pregnancies are usually possible. A small catheter (1 mm in diameter) is inserted into the femoral artery at the level of the groin under local anesthesia. Under imaging guidance, the interventional radiologist will enter selectively into both uterine arteries and inject small (500 µm) particles that will block the blood supply to the fibroids. A patient will usually recover from the procedure within a few days. The UAE procedure should result in limited blood supply to the fibroids which should prevent them from further growth, heavy bleeding and possibly shrink them.

In 1994, Dr. Bruce McLucas pioneered the first successful Uterine Artery Embolization (UAE) procedure in the United States. Since then, he has successfully performed UAE on thousands of patients worldwide. He is one of the few gynecologists in the world with the expertise to perform UAE. Dr. McLucas also trains physicians throughout the world to successfully perform UAE.

Uterine artery ligation

Uterine artery ligation, sometimes also laparoscopic occlusion of uterine arteries are minimally invasive methods to limit blood supply of the uterus by a small surgery that can be performed transvaginally or laparoscopically. The principal mechanism of action may be similar like in UAE but is easier to perform and fewer side effects are expected.^[63][64][65] UAE currently appears much more effective than this method in direct comparison.^[66]

Radio frequency ablation

Radiofrequency ablation is a minimally invasive treatments for fibroids.^[67] In this technique the fibroid is shrunk by inserting a needle-like device into the fibroid through the abdomen and heating it with radio-frequency (RF) electrical energy to cause necrosis of cells. The treatment is a potential option for women who have fibroids, have completed child-bearing and want to avoid a hysterectomy.

Myomectomy

Myomectomy is a surgery to remove one or more fibroids. It is usually recommended when more conservative treatment options fail for women who want fertility preserving surgery or who want to retain the uterus.^[68]

There are three types of myomectomy:

·         In a hysteroscopic myomectomy (also called transcervical resection), the fibroid can be removed by either the use of a resectoscope, an endoscopic instrument inserted through the vagina and cervix that can use high-frequency electrical energy to cut tissue, or a similar device.

·         A laparoscopic myomectomy is done through a small incision near the navel. The physician uses a laparoscope and surgical instruments to remove the fibroids. Studies have suggested that laparoscopic myomectomy leads to lowermorbidity rates and faster recovery than does laparotomic myomectomy.^[69]

·         A laparotomic myomectomy (also known as an open or abdominalmyomectomy) is the most invasive surgical procedure to remove fibroids. The physician makes an incision in the abdominal wall and removes the fibroids from the uterus.

Laparoscopic myomectomy has less pain and shower time in hospital than open surgery.^[70]

Hysterectomy

Hysterectomy was the classical method of treating fibroids. Although it is now recommended only as last option, fibroids are still the leading cause of hysterectomies in the US.

Endometrial ablation

Endometrial ablation can be used if the fibroids are only within the uterus and not intramural and relatively small. High failure and recurrence rates are expected in the presence of larger or intramural fibroids.

Magnetic resonance guided focused ultrasound

Magnetic resonance guided focused ultrasound, is a non-invasive intervention (requiring no incision) that uses high intensity focused ultrasound waves to destroy tissue in combination with magnetic resonance imaging (MRI), which guides and monitors the treatment. During the procedure, delivery of focused ultrasound energy is guided and controlled using MR thermal imaging.^[71] Patients who have symptomatic fibroids, who desire a non-invasive treatment option and who do not have contraindictions for MRI are candidates for MRgFUS. About 60% of patients qualify. It is an outpatient procedure and takes one to three hours depending on the size of the fibroids. It is safe and about 75% effective.^[72] Symptomatic improvement is sustained for two plus years.^[73] Need for additional treatment varies from 16-20% and is largely dependent on the amount of fibroid that can be safely ablated; the higher the ablated volume, the lower the re-treatment rate.^[74] In comparison to available treatment options, the cost effectiveness of MRgFUS in the U.S. and U.K. has been found to be reasonable and comparable to alternative treatments (hysterectomy, pharmacotherapy, uterine artery embolization).^[75][76] There are currently no randomized trial between MRgFUS and UAE. A multi-center trial is underway to investigate the efficacy of MRgFUS vs. UAE.

Epidemiology

Globally approximately 235 million people are affected with uterine fibroids as of 2010 (6.6% of females).^[77] About 20–40% of women will be diagnosed with leiomyoma at some point in their life but only a fraction of those will cause problems or require treatment.^[3]

Leiomyomata are more common in obese women.^[78] Fibroids are dependent on estrogen and progesterone to grow and therefore relevant only during the reproductive years, they are expected to shrink after menopause.

United States

Eighty percent of African American women will develop benign uterine fibroid tumors by their late 40s, according to the National Institute of Environmental Health Sciences.^[79] African American women are two to three times more likely to get fibroids than Caucasian women.^[78][80][81] In African-American women fibroids seem to occur at a younger age, grow more quickly, and are more likely to cause symptoms.^[82] This leads to higher rates of surgery for African Americans, both myomectomy and hysterectomy.^[83] Increased risk of fibroids in African- Americans causes them to fare worse in in-vitro fertility treatments and raises their risk of premature births and delivery by Cesarean section.^[83]

It is unclear why fibroids are more common in African American women. Some studies suggest that black women who are obese and who have high blood pressure are more likely to have fibroids.^[83] Black women consume fewer servings of dairy than white women and have lower intake of calcium, magnesium and phosphorus, while some data suggest that increased dairy intake in African American women is associated with lower risk of fibroids.^[84] A relation between the use of hair relaxers and risk of developing fibroids has been found, high prevalence of the use of hair relaxer among African American women may explain some of the risk.^[85]

Prognosis

About 1 out of 1000 lesions^[5] are or become malignant, typically as a leiomyosarcoma on histology. A sign that a lesion may be malignant is growth after menopause.^[5] There is no consensus among pathologists regarding the transformation ofleiomyoma into a sarcoma.

Metastasis

There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can be dangerous depending on their location.^[18]

See extrauterine fibroids.

http://en.wikipedia.org/wiki/Uterine_fibroid

Immune Aspects of Infertility

INTRODUCTION

Spermatozoa have an unusual relationship with the immune systems of both men and women. Although they are produced by men, they bear new developmental antigens to which the male immune system is not tolerant. In women, spermatozoa periodically invade their bodies as foreigners. Spermatogenesis begins during puberty, long after the immune system has learned to distinguish the antigenic expression of its own tissues and extracorporeal antigens. Despite the occurrence of new developmental antigens on sperm,¹ an autoimmune response against spermatozoa is uncommon, occurring only in approximately 7–8% of unselected men from infertile couples.²

After their intravaginal deposition, spermatozoa pass through various compartments of the female reproductive tract that are capable of mounting an immune response yet fail to elicit one.^3, 4 Clues to both the male's and female's lack of immunologic responsiveness to sperm reside within the immune system itself. Immunosuppressive factors exist within seminal fluid, and a population of T-suppressor lymphocytes has also been detected both within seminal fluid and in the interstitium of the testis and the submucosal regions of the epididymis.^5, 6

It has been known since the late 19th century that spermatozoa are antigenic and that experimental animals can be immunized with sperm.^7, 8 In nonhuman species, these immunized animals exhibit diminished fertility.^9, 10, 11 Although preliminary evidence suggested an association between the presence of circulating antisperm antibodies in men and women and infertility, it has only been in recent decades that many of the concepts dealing with immune-mediated reproductive impairment have been clarified.

The concept of immunologic infertility stems from several key observations. It was demonstrated in the 1950s that autoimmune responses to sperm and testis antigens had immunologic consequences. Guinea pigs immunized with homologous testis antigens in complete Freund's adjuvant developed autoimmune responses to the antigens, leading to orchitis and aspermatogenesis.¹² The clinical relevance of antisperm autoimmunity became apparent in 1959, when spontaneous agglutination of ejaculated sperm and serum antisperm antibodies were observed in infertile men by Rumke and Hellinga.¹³ During the same period, Franklin and Dukes¹⁴ noted the presence of sperm agglutinating activity in sera of women with unexplained infertility. This was soon followed by the detection by Fjallbrant¹⁵ and Isojima and colleagues¹⁶ of serum antisperm antibodies that promoted complement-dependent sperm immobilization in infertile women. When endocrinologic problems of ovulation, sequelae of genital tract infections, and abnormalities of sperm production are excluded, there remain a substantial number of patients with idiopathic infertility. In this group, antisperm antibodies appear to have an important etiologic role.¹⁷

DIAGNOSIS OF IMMUNITY TO SPERM: PRINCIPLES

Proof that antisperm antibodies have a role in infertility requires documentation of their presence in sera of men and women, demonstration of these immunoglobulins bound to the sperm surfaces, as well as evidence of an alteration in the ability of such immunoglobulin-coated sperm to function – that is, to enter the female reproductive tract and either to reach the site of fertilization or to fertilize eggs.

Until the late 1970s, most laboratories attempted to diagnose immunities to sperm by using one of three major forms of serologic tests: sperm agglutination (either macroscopic or microscopic), complement-dependent sperm immobilization, or indirect immunofluorescence. Although several studies documented a clear difference in the prevalence of antisperm antibodies in sera of infertile couples as compared with fertile men and women, other studies could not make this distinction between groups. The range of positive results for agglutination assays has varied from 2% to more than 30%, with a large overlap between fertile and infertile groups (Table 1). Although complement-dependent immobilization provided more discriminating power, in that the incidence of false-positive results was far lower in sera of fertile men and women, this test suffered from an inability to detect noncomplement-fixing immunoglobulins, such as IgA.^18, 19 Also important was the realization that naturally occurring antisperm antibodies exist in many species, including humans, at low titer. The sera of approximately 60% of men and women possess immunoglobulins that react with sperm, as detected by indirect immunofluorescence.²⁰ These naturally occurring antibodies are readily absorbed by spermatozoa and testicular extracts but not by other human tissue. Of importance, they do not stain the surface of viable sperm in suspension but rather are directed against intracellular antigens of methanol-fixed permeabilized sperm. In one study, sera possessing antiacrosomal antibodies, when absorbed with bacteria of several species, no longer reacted with sperm. These naturally occurring antisperm antibodies have been shown to be present at only low titer (only 3 of 80 sera were positive at 1:16 or greater).²¹ In contrast to their high incidence in the general population, antibodies directed against antigens of the sperm surface, as detected by agglutination tests, mixed agglutination reaction, and immunobead binding, are uncommon and present at high titer in less than 10% of infertile men and women.²²

Methods for Detecting Antisperm Antibodies on Sperm
Several methods are now clinically available to determine whether spermatozoa themselves are coated with immunoglobulins. These include a direct antiglobulin assay using ¹²⁵I radiolabeled heterologous antibodies, a direct enzyme-linked immunosorbant assay (ELISA), mixed agglutination reaction, and immunobead binding.^{23, 24, 25, 26} Although each of these tests allows one to determine, in a semiquantitative way, the extent of autoimmunity to sperm, immunobead binding in particular provides a measure of the proportion of spermatozoa in the ejaculate coated with each of three immunoglobulin classes (IgG, IgA, and IgM). The precise amount of immunoglobulin associated with an individual spermatozoan surface, however, still cannot be determined by current methods.
Immunobead binding uses micrometer-size plastic microspheres to which antibodies produced against human antibodies are chemically coupled.²⁷ The antihuman antibodies on the immunobead surface bind to the human antibodies present on the sperm surface. Hence, they act as antibody detector particles, which can be visualized with an ordinary microscope. This test can be used to analyze sperm recovered from semen specimens and can be used indirectly to study serum for the presence of antisperm antibodies. In the latter case, spermatozoa must first be documented free of antibodies on their surface, by a direct immunobead assay. They are incubated in serum at various dilutions and subsequently washed free and retested to determine if they have acquired antibodies on their surface during this time. Immunobead binding allows one to determine the proportion of sperm that is coated with antibodies, the region of the sperm surface to which antibodies bind (head versus tail), and the immunoglobulin class (IgG, IgA, or IgM) of antibody present.

DETECTION OF HUMORAL ANTISPERM ANTIBODIES

Antibodies that mediate sperm immobilization through their interaction with complement were initially described by Fjallbrant in 1968¹⁵ and Isojima and colleagues in 1968.¹⁶ In these assays, sperm are washed and incubated with serially diluted heat-inactivated test serum or secretions. A source of complement, usually guinea pig serum, is added. A time end point for immobilization of 90% of sperm or the percentage of motile sperm at a standard time is compared microscopically with sperm incubated with control sera and complement alone. Complement-dependent immobilization, although highly specific in that false-positive reactions are uncommon, does not detect the presence of non-complement-fixing immunoglobulins, such as IgA. The amount of antibody present in the sperm surface also appears to have a role in the extent of complement-dependent immobilization (Table 2).¹⁹ Hence, results obtained from these tests have a definite relationship to immunologic infertility and are highly specific. However, not all antisperm antibodies are detected. In addition, because seminal plasma contains complement inhibitors, complement-dependent cytotoxicity tests cannot be applied to detection of autoantibodies to sperm in semen...

http://www.glowm.com/section_view/heading/Immune%20Aspects%20of%20Infertility/item/328