Evaluation and Management of the Infertile Couple
Introduction
Infertility is defined as the inability to conceive after trying for one year.
Recent studies show that around 15% of couples need some kind of medical assistance in order to conceive a child. The incidence of infertility has increased in the last few decades, owing to socio-medical issues such as previous pelvic surgery, pelvic infections due to the use of intrauterine (IUD) devices, miscarriages and elective abortions, sexually transmitted diseases, the stress of everyday life, and the voluntary postponement of reproduction until a later age when a career is well established or until financial stability is reached, among other reasons. The purposes of this article are: to review the most common causes of infertility, explain how the couples are evaluated, and discuss various therapeutic alternatives.
The Etiology of Infertility
There are six causes, areas or factors which can make it difficult for a couple to achieve a pregnancy.
1. Male Factor: the husband is considered to have a normal fertility potential if the analysis of his semen shows a volume of 1-5 mL, the sperm count is above 20 million per milliliter, sperm motility is greater than 40% and if more that 30% of his sperm exhibit normal morphology (form and structure). Quite frequently we see patients with oligospermia (low sperm count) or an absence of sperm in the ejaculate (azoospermia), asthenospermia (low motility), and/or teratospermia (high count of malformed sperm).
If the semen analysis is abnormal, the most common causes are: varicocele (varicose veins around the testicle), prostatitis and genital infections, hormonal imbalances, congenital conditions, recreational drugs, and medications.
2. Cervical Factor: the cervical mucus or secretions present in the neck of the womb play a very important role in reproduction. Halfway through the menstrual cycle (at the time of ovulation) the cervical mucus becomes abundant, elastic, liquid, and penetrable by sperm, with an alkaline pH and without white blood cells.
The most common causes of hostile (not receptive) mucus are: infection (cervicitis), low level of estrogen (an ovarian hormone that triggers the normal changes in preovulatory mucus), absence of mucus due to surgery or previous cervical cryotherapy, very low acidity and pH, antisperm antibodies (allergic reaction to sperm), and stenosis (narrowing of the cervical canal).
3. Uterine Factor: the conditions of the womb which most often interfere with reproduction are: myomas (fibroids), infection (endometritis), congenital anomalies and Asherman's syndrome (intrauterine adhesions or scarring, usually after a miscarriage, a dilation and curettage, or a Cesarean section).
4. Tubal Factors: obstructions of the fallopian tubes are the most common causes of infertility. Blockages of the tubes are most often due to inflammatory processes, such as infections caused by an IUD, abortion or postpartum complications, appendicitis, post-operatory peritonitis, sexually transmitted diseases, or tubal polyps. The obstructions of the fallopian tubes due to previous sterilization or endometriosis are frequent issues. Nowadays pelvic tuberculosis is rare.
5. Ovarian Factor: Ovulation irregularities are very common. Patients who do not ovulate regularly (anovulatory) usually have irregular menstrual cycles, frequently are overweight and have an abundance of body hair. Their ovaries present a polycystic appearance and for this reason they undergo unnecessary surgeries. Ovulation problems and the Stein-Leventhal syndrome are due to imbalances in the frequency and range of hormone pulses in the hypothalamus and the pituitary glands.
Other hormonal imbalances are caused by thyroid gland problems, prolactin (a pituitary hormone related to the production of breast milk), an excess of androgenic (masculine) hormones, being underweight or overweight (adipose tissue), recreational drugs, medications, physical exercise-induced stress (sports), or emotional distress.
6. Peritoneal Factor: The peritoneum is the membrane or layer that covers the surface of the internal organs. Pelvic adhesions (scar tissue) and endometriosis are assigned to this factor. Adhesions usually occur between the tubes and the ovaries, peritoneum, intestines, uterus or other organs. Adhesions affect fertility by interfering with the normal function of the tubes, which is to retrieve and transport the eggs and the sperm so that fertilization can take place. Adhesions generally follow an inflammatory process (an infection), a post-surgical complication, or are due to endometriosis.
Endometriosis is a condition in which the same tissue that constitutes the internal layer of the uterus (the endometrium) develops in places where its presence is not normal. This tissue should only be found in the uterine cavity and not in the fallopian tubes, ovaries, peritoneum, etc. The prevalent theory is that this condition occurs when a retrograde menstruation (a backflow of menstrual blood) carries these cells internally through the tubes. This displaced or ectopic tissue growth is very irritating and the cause of adhesions, as well as anatomical and functional disorders.
Incidence
The frequency of these factors in cases of infertility is:
1. Male factor - 40%
2. Cervical factor - 5%
3. Uterine factor - 8%
4. Tubal factor - 20%
5. Ovarian factor - 25%
6. Peritoneal factor - 25%
Collectively, these incidences add up to more than 100%, because in 25% of couples, more than one factor is involved.
Evaluation of Infertility
1. The masculine factor is evaluated using computerized semen analysis. Normal values were explained in a previous section. Usually two or three analyses should be obtained to derive a baseline, since the variation between tests can be considerable. Here in the PRFC, this lab study is done using the CASA (“Computer Assisted Semen Analysis”) method, which is the most objective, consistent and reliable, allowing us to evaluate important parameters such as linear sperm velocity, hyperactivation and strict morphology. The patient will be given a physical exam by an urologist or by means of ultrasound to detect the presence of a varicocele or any problems involving the prostate gland, the testicles or the vas deferens (semen ducts). The next step consists of obtaining blood samples to test for follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T), to detect any hormonal imbalances. Less frequently we require thyroid function, prolactin and antisperm-antibody tests.
A semen culture is indicated in the case of patients whose semen has bacteria, or an elevated white blood cell count. An analysis of the fructose in the semen is ordered for patients with azoospermia (absence of sperm). Fructose is a sugar secreted by the seminal vesicles and its absence in the semen indicates an obstruction of the ejaculatory ducts. If an obstruction of the vas deferens is suspected, a vasogram or X-ray of the duct will be done following injection of a radio-opaque contrast fluid. Sometimes it is necessary to do a testicular biopsy in order to evaluate its anatomy and functioning.
2. Post-coital test (PCT): a test that is used to evaluate sperm function, the cervical mucus and their mutual compatibility. The PCT is done halfway through the menstrual cycle, in one of the three days before ovulation. It consists of examining the patient within the first twelve hours after sexual intercourse to obtain a sample of her cervical mucus. The mucus is studied under the microscope to evaluate its normal characteristics and the presence, amount and motility of the sperm.
In a normal PCT, we should see at least seven sperm per field with progressive linear motility. If infection and white blood cells are found in the mucus, cervical cultures will be obtained. We sometimes find mucus that is apparently normal but the sperm are dead, possibly due to an acidic pH, or antisperm antibodies.
3. The uterine cavity, fallopian tubes and peritoneum together comprise the pelvic factor. The hysterosalpingogram (HSG) is a radiographic test that allows us to evaluate the intrauterine and intratubal anatomy to detect anomalies in the architecture of the womb and to determine if the fallopian tubes are open and, if they are not, to localize where the obstruction is. This study requires threading a thin tube through the cervix to introduce a radio-opaque fluid. The radiographic dye fills the uterine cavity and then passes through the fallopian tubes to the peritoneal cavity. The HSG test is done during the seven (7) days that follow the end of the menstrual period. If a uterine abnormality were found, a hysteroscopic evaluation would be indicated. A hysteroscopy is a minor surgical procedure (done in the Operating Room, under general or local anesthesia) and it is similar to a cystoscopy. A small telescopic instrument is introduced through the cervix to visualize the uterine cavity. This way, the inside of the uterus can be checked, and certain uterine conditions can be diagnosed and operated on, under direct visualization.
4. A laparoscopy is a minor surgical procedure frequently utilized to evaluate the pelvic organs of an infertile patient. A telescopic tube is introduced though the umbilicus (belly button) in order to see inside the peritoneal cavity. This procedure, which takes between 30 and 60 minutes, can be done in the Operating Room, under general anesthesia, but on an outpatient basis. Diagnostic laparoscopy allows us to evaluate a womans anatomy without the need for exploratory surgery. Endometriosis, pelvic adhesions, anomalies of the fimbriae and tubal inability to retrieve the eggs after ovulation are all conditions that can only be diagnosed with precision through the laparoscope. Tube patency (permeability) is checked under direct visualization by means of a blue dye (methylene blue) introduced through the cervix and uterus. Operative laparoscopy allows us to carry out a limited number of surgical procedures, for example, fulguration of superficial endometriosis and lysis (division) of pelvic adhesions to correct most pelvic conditions. Endoscopy photographs, video and DVDs are made to document the case and instruct the patient.
5. There are several ways of documenting ovulation: the oldest is measuring basal temperature. Body temperature upon awakening, before any physical activity, is lower than 98 degrees before ovulation, and then it remains above 98 degrees for 12 to 14 days after ovulation, due to increasing levels of progesterone, the ovulation hormone. A biphasic pattern indicates the woman has ovulated. Keeping track of basal temperatures is a tedious chore, it increases the patients anxiety, it is not a precise method of determining the day of ovulation, and ought not to be used to schedule sexual intercourse or insemination. It is an old-fashioned method rarely used any more in contemporary medicine. Nowadays ultrasound scanning plays an essential role in the evaluation of follicular development and ovulation monitoring. Another method of checking ovulation is measuring levels of progesterone in the blood. The sample is obtained seven days before the expected menstruation date (seven days after ovulation) and the values obtained should be above 12ng/mL. The best ovulation test is a biopsy of the endometrium, which entails obtaining a tissue sample from the internal layer of the uterus. This biopsy is done in our medical offices, two or three days before menstruation. The pathologist does a histological assay of the tissue sample and detects if ovulation has taken place, how many days post-ovulation the endometrium has been developing, and indicates the presence of endometritis or inflammation or any other condition that can affect the implantation of a fertilized egg, such as an absence of integrins (binding molecules).
6. Lab tests: The four basic lab tests that should be done for all patients are: prolactin, DHEA-sulphate, TSH, and CA125 (please refer to the article on Evaluation of Endometriosis). Depending on the diagnosis, it may be necessary to test for androgens, blood sugar, insulin, FSH, LH and/or sperm antibodies, as well as perform endometrial or cervical cultures, a pelvic ultrasound to evaluate follicular development, hydrosonograms and X-rays or computerized tomography (CT) scans of the pituitary gland.
7. Summary: When patients have regular menstrual cycles, the evaluation is scheduled as follows: the patient calls our office when her period begins, to receive her instructions. The husband is requested to give a semen sample (after three to five days of abstinence). The PCT is done between day 12 and day 14 of the menstrual cycle (or a different day, depending on ovulation); either a biopsy of the endometrium is obtained (days 25 to 27 of the cycle) or a progesterone test (days 20 to 22). During the following cycle the HSG is performed when menstruation ends. A laparoscopy is indicated when a pelvic problem is suspected or discovered, if the results of the CA125 are elevated, or if the evaluation has been negative up to that point. Further tests or assays are ordered if and when other positive factors are discovered.
In patients with irregular cycles, or in cases of long-term infertility, the first goal is to stimulate ovulation (usually with clomiphene citrate) and, when ovulation has become regular, we proceed as outlined above. The evaluation of infertility should not take more than six to eight weeks. Nowadays, with the vast diagnostic armament available, the cause of infertility should be determined in more than 98% of patients, and we should rarely have patients who present idiopathic, unexplained or inexplicable, infertility.
Treatment
Almost all of the causes of infertility (with the exception of certain congenital abnormalities) are susceptible to treatment, either medical or surgical. In this rather limited space it is not possible to go into detail about all the treatments available, but it is worth mentioning that more than 50% of the patients who seek specialized treatment do become pregnant.
1. In the case of couples whose infertility is due to the male factor, the most frequently-used treatments are: varicocelectomy, hormonal treatment with clomiphene citrate, chorionic gonadotropic hormone (hCG), antibiotics and artificial insemination (with the husband's or donated sperm). Artificial insemination using the husband's semen is the area where the majority of medical advances have occurred in the last few years. Inseminations are simple, medical-office procedures that consist of the introduction of semen in the female tract. (See accompanying article.)
2. Cervical factor problems are treated by dilating cervical stenosis (narrowness), estrogen therapy or ovulation stimulation, antibiotics, vaginal douching with sodium bicarbonate (baking soda) or by intrauterine inseminations.
3. Uterine problems usually require surgery to correct myomas, adhesions or congenital anomalies.
4. During the last decade, advances in pelvic reconstructive microsurgery techniques have yielded unprecedented successes. The use of the microscope or surgical magnification, better sutures (being able to avoid chromic or non-absorbable sutures), special instruments that do not injure the tissues, the use of medication to prevent post-surgical adhesions, complete removal of diseased tissue, and a perfect realignment of the tissues have all resulted in a much better restoration of the anatomy, and a greater percentage of clinical pregnancies.
Reanastomosis, or the reconnection of the fallopian tubes in previously sterilized patients, is one of the most common and successful microsurgeries in more than 80% of selected cases.
5. The treatment of ovulation problems has become routine, and simplified by ultrasound monitoring of follicle growth. (Please refer to the article.)
Ovulation can be achieved in almost 95% of patients using clomiphene citrate, letrozole (Femara), follicle-stimulating hormone (FSH, Follistim, Gonal F, Bravelle, Menopur), hCG (Novarel, Pregnyl), bromoergocriptine (Parlodel or Dostinex), corticoids (Decadron), insulin-sensitizing agents (Metformin) or a combination of these. Wedge resection of the ovaries is rarely called for in current medical practice.
6. In vitro fertilization and intra-fallopian fertilization are specialized treatments that employ more sophisticated technologies to relieve infertility problems. (See accompanying IVF Brochure.)
Computerized semen analysis
The male factor is evaluated by means of semen assays. Here in the PRFC we employ a technique which is known as CASA, or Computer Assisted Semen Analysis, which uses computer-controlled equipment to do the study. This state-of-the-art technology employs the most objective, consistent and reliable method available. In addition to its more precise determination of the basic parameters, it allows us to evaluate other aspects that are important for fertility, such as linear sperm velocity, hyperactivation and strict sperm morphology.
The semen sample is obtained by masturbation, after three to five days of sexual abstinence. A long abstinence, greater than seven days, usually reflects a falsely-diminished sperm motility. Shorter abstinence periods may result in low ejaculate volume and a diminished sperm count, if not enough time has gone by to allow for replenishment.
In 1999, the World Health Organization established that a normal semen analysis must have:
- ejaculate volume, between 1 and 5 mL
- sperm count, over 20 million per milliliter and over 40 million per ejaculate
- rapid progressive motility above 40%
- conventional sperm morphology greater than 30%, or, 14% if using Strict Criteria.
Usually two or three analyses will be obtained to produce a baseline, since the biologic variation between tests can be considerable.
Post-coital test
The PCT is a test that is used to evaluate sperm function, cervical mucus patency and compatibility between these two, and the success or failure to deposit a sufficient amount of sperm in the female tract during sexual intercourse. The PCT is done halfway through the menstrual cycle, in one of the three days before ovulation (when a mature follicle can be detected in the ovaries). It consists of a vaginal examination of the patient within the first twelve hours after sexual intercourse to obtain a sample of her cervical mucus (very similar to Pap or cancer tests). The mucus is studied under the microscope to evaluate its normal physical characteristics (amount, liquidity, elasticity and pH) and the presence, amount and motility of the sperm.
In a normal PCT, at least seven sperm per field with progressive linear motility should be observed.
Hysterosalpingogram
The hysterosalpingogram (HSG) is a radiographic test that allows us to evaluate the anatomy within the uterus and the fallopian tubes. This study requires threading a thin tube through the cervix to introduce a radio-opaque fluid. This radiographic dye fills the uterine cavity and then passes through the tubes to the cavity formed by the peritoneal membrane. It's a very valuable study that allows us to check the size and shape of the uterine cavity, detect anomalies in the architecture of the womb (either congenital, or due to myomas, adhesions or polyps) and determine the patency of the fallopian tubes, to diagnose whether the tubes are open and, if they are not, localize where the obstruction is. The HSG test is done during the seven (7) days that follow the end of a menstrual period.
The hydrosonogram test is similar to the HSG but it is done in the medical office, using ultrasound. This study entails introducing saline solution or a sterile fluid in the uterine cavity to check its contours and content. The fallopian tubes cannot be visualized by hydrosonogram.
Ovulation stimulation
Treatments that induce ovulation are very common, because one out of every four patients with infertility problems is not ovulating well. The success rate in patients treated for ovulation issues reaches almost 95%. We can choose among a considerable array of fertilizing medications which stimulate the growth of eggs in the ovaries, such as:
Fertility pills:
clomiphene citrate (Clomid, Serophene), letrozole (Femara)
Fertility injections:
follicle-stimulating hormone (FSH, Follistim, Gonal F, Bravelle, hMG,Menopur)
Ovulation injections:
hCG (Novarel, Pregnyl)
Adjuvant (aiding) Therapies:
bromoergocriptin (Parlodel or Dostinex),
corticoids (Decadron),
insulin-sensitizing agents (Metformin) or combinations of these.
Wedge resection of the ovaries is rarely called for in modern medicine.
Ultrasound monitoring of follicular development has simplified the evaluation of ovarian response to medication and of follicular growth, and is a valuable aid in determining the moment of ovulation and the timing of the post-coital test, insemination, and the window of fertility.
Endometriosis
Endometriosis is a medical condition defined by the presence of endometrial tissue and glands growing outside of the endometrial cavity and the uterine muscle. The endometrium is the innermost layer of the uterus, the tissue that is produced, grows and sloughs off every month during a menstrual period. This endometrial tissue is made up of glands and stroma (supporting tissue), and its presence is normal only in the uterus. In its normal place, within the womb, it is called the endometrium. When it grows elsewhere, for example in the peritoneal membrane, the ovaries, fallopian tubes or distant tissues, it is known as endometriosis.
Theory
Endometriosis was first described in the medical literature in the 1800s. The disorder did not acquire importance until 1927, when Sampson published his theory of retrograde menstruation as the main cause of the origin of endometriosis. During menstruation, fragments of endometrial tissue flow backwards, through the fallopian tube, to the internal peritoneal cavity. This endometrial tissue can transplant itself internally, giving rise to an ectopic or displaced endometrium. We know, clinically, that during menstruation blood can be found in the abdomen, as a result of a reflux through the fallopian tubes. It is generally found in the dependent parts of the pelvic organs, where it settles by gravity. It can also occur in women whose cervical canal is narrow or who have an obstruction to the normal flow of menstrual blood, and in patients in whom absence of the cervix or of the vaginal septa results in an increased reflux of retrograde menstruation.
Endometriosis can occur in patients who have a congenital obstruction of the fallopian tubes, and in distant places, such as the lungs, kidneys, and even the brain. It is believed that in these cases fragments of the endometrium transplant themselves to distant areas, transported by the bloodstream or the lymphatic system.
The third theory of the origin of endometriosis postulates it is a transformation of the peritoneum, the membrane that covers the internal organs, towards endometrial tissue. Embryologically, the peritoneum was one of the originating cells of the endometrium and, through some unknown stimulus, that mature peritoneoum can become once again endometrial tissue, a situation that can occur in men who have been undergoing estrogen therapy.
Even though 90% of women bleed endometrial blood back into the peritoneum during their periods, endometriosis does not develop in more than a small percentage of them. At present it is believed that there are genetic or immunologic factors that influence a woman's susceptibility to developing this disorder.
Endometriosis is a very common condition in women. It is estimated that between 3% and 19% of women of reproductive age and 25% to 35% of infertile women present with endometriosis. Formerly, doctors believed endometriosis affected mostly career women, professionals over 30 years of age. Even though 29 is the average age at which endometriosis is diagnosed, it tends to start in adolescence. It cannot appear before puberty, but it can last beyond menopause. The incidence of endometriosis is found in equal proportion in patients of all races and social class.
Symptoms
The classic symptoms of endometriosis are pelvic pain and infertility. It should be suspected in any patient who complains of significant dysmenorrhea (pain during menstruation), dyspareunia (difficult or painful sexual intercourse), or in any patient with chronic pelvic pain, whether it's cyclical or continuous. There is no direct relation, however, between the extent of the endometriosis and the severity of the symptoms. The pain depends on the localization of this condition and how actively the endometriosis is producing inflammation-causing substances that will be described below. Women who present minimal endometriosis implants can suffer severe or incapacitating pain, whereas others, with advanced cases, could have no symptoms at all. There are other, rarer symptoms that occur when the urinary or gastrointestinal systems are involved. The patient may have blood in the urine during menstruation, diarrhea and rectal bleeding, constipation, and painful bowel movements, mostly during her period. These symptoms suggest an active implantation of endometrial tissue in the urinary or gastrointestinal epithelium (the tissue that covers a surface). Pulmonary endometriosis can cause respiratory difficulty, pleural effusions or pneumothorax, and the coughing of blood during menstrual periods. Endometriosis of the central nervous system can cause sciatica, neuralgia or convulsions. Lower back pain and irregular spotting before periods are quite common symptoms of endometriosis. Endometriosis turns out to be a very common cause of infertility in women. Several population studies have shown that, in 25% to 50% of couples who are infertile, the female partner has endometriosis. And yet, only 30% to 50% of women who are affected with endometriosis are infertile, which indicates that the condition is not synonymous with infertility, although the probability is quite high.
When endometriosis is the cause of infertility, any number of mechanisms could be at work. Without a doubt, in advanced stages of endometriosis, the adhesions and distortion of the anatomy impede the passage of the egg from the ovary and its capture by the fallopian tube. These cases are classified as a mechanical infertility caused by endometriosis.
In milder cases of endometriosis this anatomical bottleneck caused by adhesions does not exist. Infertility in these cases is due to hormonal and functional causes. Endometrial tissue produces a series of proteins that interfere with the normal retrieval of the egg by the fallopian tube. Peritoneal fluid in patients with endometriosis contains substances that are toxic to the egg; proteins that block fertilization and others that interrupt the normal development of the fertilized egg. Peritoneal fluid also contains an elevated amount of macrophage cells (white blood cells from the immune system), which produce most of the toxic substances that inactivate and ingest (phagocytize) the sperm. Endometrial tissue, in tandem with macrophage cells, produces high levels of prostaglandins, hormones that affect the pelvic environment and accelerate the transport of eggs through the fallopian tubes, causing the fertilized egg to arrive in the uterus prematurely.
In the last few years researchers have paid a lot of attention to alterations of the immune system in patients with endometriosis, and the way fertility declines, affecting the implantation of the embryo in the uterus. When this patient conceives, these antibodies can affect the site where implantation occurs, thus increasing the risk of spontaneous abortion.
Classification
Endometriosis is classified according to the quantity and the places where endometriosis implants are located, as well as the pathology of the adhesions associated with the affected organs. The most widely used classification or rating system is the one developed by the American Society for Reproductive Medicine (ASRM), which assigns a score by area and location of the endometriosis implants. It groups patients into four categories, called stages, numbered one, two, three and four, which correspond to minimal, mild, moderate and severe endometriosis.
Diagnosis
The diagnosis is arrived at by means of a laparoscopy. This is a minor surgical procedure done under anesthesia, to introduce a thin tube and telescopic lens that permits evaluation of the internal structures. Sometimes endometriosis is diagnosed during the course of major surgery being done for other reasons. While it can be suspected, it cannot be diagnosed with certainty just by studying the medical history, or a pelvic exam, or even ultrasonography. More recently the CA125 test has been used to help diagnose endometriosis. CA125 is a protein, derived from the tissue that covers internal organs such as the peritoneum and the endometrium. The letters CA stand for cancer antigen, because it was discovered in patients who had malignant tumors of the ovaries. In these cases the antigens are conspicuously elevated. Patients with endometriosis also show a mild to moderate elevation of the CA125 antigen. Normal results in this test are all values below 16 units. In patients with endometriosis we usually find values between 20 and 100, whereas patients with malignant ovarian tumors usually exceed 1000 units. The levels of CA125 correlate with the stages of the disease; they can also be used to measure the patient's response to a treatment. The results of a CA125 test, however, are not absolute; they offer a sensitivity of 85% and 15% false negatives.
Treatment
The treatments for endometriosis can be divided in three groups: surgical, medical, and a combination of both. The choice will depend upon several factors: whether the goal is to alleviate symptoms only, if there is a concomitant infertility problem, the age of the patient, how many years the condition has persisted, and the response to previous treatments. Surgical treatments are the most effective ones, particularly in the most advanced stages of endometriosis.
Surgical
Surgical treatments are subdivided into laparoscopies and major surgery. In most cases endometriosis can be and should be eliminated during a laparoscopic diagnostic procedure. Endometriosis implants can be eliminated using bipolar electrocauterization, endo-coagulation, by means of laser therapy, or by resection (removal). The technique most often used is electrocauterization with bipolar energy, during which an electrical current is applied to the growths, destroying the abnormal tissue and clotting the implants without compromising the peritoneal membrane. An alternative is to use Ultracision technology (Harmonic Scalpel), which consists of applying ultrasound waves with special instruments to clot and vaporize the implants and abnormal tissues. These are the preferred methods to treat endometriosis cases, because abnormal tissues are completely removed in a minimally invasive procedure with the least possible trauma to adjacent tissue. Adhesions can be cut away with scissors or Ultracision and the anatomy can be restored, in a majority of cases, using surgical laparoscopy. Laser surgery had its heyday years ago, but is seldom used any more because lasers can be dangerous to the patient, and they produced defects and perforations in the peritoneal membrane, leading to sub-optimal results.
In those cases where the anatomical alterations are greater or the endometriosis implants and adhesions are compromising vital organs such as the bladder or intestines, major surgery is considered. It is advisable to use microsurgical techniques to minimize surgical trauma to healthy tissue, excise all diseased tissue and reduce the likelihood of post-surgical adhesions. Systemic medication administered intravenously is used during and after the surgery to reduce the probability of adhesions. Intraperitoneal membranes or fluids are placed on the tissues during the operation to enhance healing of the organs.
Patients who have suffered a great deal of pain associated with endometriosis are counseled to undergo, at the same time, a presacral neurectomy, which consists of cutting the sensory endings of nerves that cover the reproductive organs. This is done during major surgery, strictly to alleviate the pain. This intervention neither increases nor decreases the probability of becoming pregnant; it does, however, bring pain relief to more than 90% of patients.
Medical
The medical treatment of endometriosis patients can be subdivided into oral, injectable and nasal inhalation therapies. Of the oral treatments, the most commonly used is danazol, a hormone that is derived, rather distantly, from androgens (masculine hormones). This medication works mainly at the pituitary gland level, to inhibit the pulse rate of hormones that produce and develop the eggs in the ovaries. Danazol exerts effects in the ovaries as well, inhibiting many hormones that are important to the production of estrogens. It also works upon the endometriosis tissues, by damaging its cells and helping the body eliminate these growths.
Leuprolide acetate and goserelin injections, as well as nafarelin nasal inhalers, are prescribed medications that work at the pituitary and hypothalamus gland levels. These medications are hormones that inhibit and disable the pituitary gland’s functions. Depending on the dosage, the estrogen levels are usually lower that those obtained using danazol. The injections can be administered daily or be depot preparations, which last four weeks in the body. Nasally inhaled medication is administered twice daily.
Side effects of these medications vary according to their source and the levels of estrogen that they cause to fluctuate in the organism. Patients who undergo these therapies frequently complain of menopause symptoms, such as hot flashes, sweat episodes, vaginal dryness, etc. These types of drugs generally suppress estrogens below 30 picograms per milliliter, which can be associated with a greater incidence of osteoporosis due to bone calcium loss. On the other hand, danazol, because it is distantly related to androgens, could cause side effects such as growth or pigmentation of some body hair, acne, oily skin, muscle cramps and weight gain. Physical exercise, such as walking one hour three times a week, practically eliminates androgenic side effects, because the body will metabolize all residues.
These medication therapies must be administered during a minimum of four months, and usually last between six and nine months. No microscopic changes signifying cell damage to endometriosis tissues will be observed until at least three months of drug therapy have been completed. The treatment is monitored by measuring estradiol levels. Irrespective of the medication chosen, the goal is to reduce the levels of estradiol to between 30 and 50 picograms. Increasing estrogen levels indicate the medication is not performing as expected and the patient either needs a different dose or a change of drug regimen. On the other hand, if estrogen levels fall below 30 picograms the patient runs a greater risk of developing side effects related to low estrogen. Extreme medical suppression of estrogens will not correct endometriosis any faster or better as long as the levels are kept under 50 picograms.
Persistent and Severe Symptoms
In late-stage endometriosis cases that are associated with severe symptoms, the definitive treatment may make it necessary to extirpate the uterus and both ovaries. This alternative is considered when the patient has completed her childbearing, or the endometriosis is seriously compromising vital organs, such as the intestines or the urinary system. When a patient has been unable to become pregnant, she is advised to try in vitro fertilization before radical surgeries are considered. Endometriosis does not reduce the efficacy of IVF treatment.
Recurrence
The probability of endometriosis recurring depends on the surgeon, the medication dosages, the duration of medical treatment and individual factors exclusive to the patient. It has been reported that typically, there is between 10% and 25% probability of recurrence in the first two years of treatment and up to 50% cumulatively. What is clear today is that in the overwhelming majority of cases of recurrence it is not that it reappeared but that it remained and persisted when the treatment, be it medical or surgical, was incomplete.
Conclusions
During the last decade, no medical study has proven that a MEDICAL TREATMENT with drug therapies increases the probability of pregnancies in infertile patients. Nowadays, drug therapies for endometriosis in infertile patients have fallen into disuse and, given the cost and side effects of the medications, these have been set aside just for ameliorating the symptoms of the condition, and no longer play an important part in the management of infertility. By the same token, major surgeries for this condition are decreasing in frequency, because a much higher rate of pregnancies in obtained using IVF in cases of severe endometriosis.
The protocol and strategies most recommended by experts in this field are:
1) Remove all visible endometriosis implants by laparoscopic techniques;
2) Stimulate ovulation with letrozole (Femara); and
3) Fertilize in vitro after a prudent wait.
Endometriosis continues to be an enigma. There are still many unanswered questions about the origin of the disease and how the immune system is involved, as well as controversies surrounding its medical and surgical management.
Intrauterine Insemination
When a woman conceives naturally, sperm travel from the vagina, through the cervix, uterus (womb), and to the fallopian tubes. If sperm reach the tube around the time of egg release from the ovary (ovulation), the sperm and egg can join, and fertilization occurs in the tube.
The cervix naturally limits the number of sperm entering the uterus. This means that only a small percentage of the sperm in the ejaculate actually make their way to the fallopian tubes. Intrauterine insemination (IUI) is a procedure that places sperm beyond the cervical opening, into a woman's uterus near the time of ovulation. This makes the passage to the fallopian tubes much shorter, and there is a better chance that the egg will encounter a greater amount of sperm. The goal of this procedure is to improve a woman's likelihood of becoming pregnant by increasing the number of sperm and shortening the route to the fertilization site.
When is IUI useful?
There are many reasons why couples have difficulty getting pregnant. IUI may be useful for some of them:
Unexplained causes.
The most common use for IUI is when no cause for infertility is found. Infertile women are recommended to take medications (orally or injections) that stimulates the ovaries to mature several eggs at once. The goal is to increase the chance of fertilization by placing more sperm in contact with more eggs.
Cervical stenosis or abnormalities.
IUI is useful when a woman's cervix has scars that prevent sperm from entering the uterus from the vagina. This is often in women who have had surgery on their cervix (cryosurgery, cone biopsy, electro-surgical excision (LEEP procedure, etc.). IUI can also help when a woman has a cervix with anatomical anomaly in such a way as to prevent sperm from passing through, such as when the cervical mucus is scant, very thick, impenetrable or acid.
Problems with sperm delivery.
IUI can also be used for couples where the male part cannot have sex or ejaculate effectively. For example, retrograde ejaculation is when sperm is released backwards into the bladder, rather than through the penis; previous surgeries or medical conditions, such as diabetes, can cause retrograde ejaculation. In addition, IUI can help if the man has an abnormal urethral opening, such as hypospadia.
Lack of ovulation (anovulation).
Most women who do not regularly ovulate, or when it is difficult to pinpoint their fertile time and need ovulatory medications, may become pregnant through intercourse, but frequently IUI may be more successful.
Fertility preservation.
Men can collect and freeze (cryo-preserve) their sperm for future use before having a vasectomy, testicular surgery, or radiation/chemotherapy treatment for cancer. Sperm can be thawed and later used for IUI.
Third-party reproduction.
IUI is used when couples use the sperm of a man who is not a woman's partner to have a baby. This is known as artificial donor insemination (AID). AID is performed when the male partner has no sperm or when sperm quality is so affected that their sperm cannot be used for conception, and/or in vitro fertilization is not an option. AID can also be used if man has certain genetic diseases that he does not want to pass on to his children. Single women or same-sex female couples who want to have a baby may also consider AID.
How are sperm collected?
The sperm needed for IUI can be collected in several ways. Usually, the man masturbates in a sterile plastic jar or container that is provided by the office or andrology laboratory (laboratory that specializes in the treatment of male fertility problems). Sperm may also be collected during sex in a special condom provided by your doctor. If a man has retrograde ejaculation, the sperm can be recovered in the lab, from the urine that has been collected after ejaculation.
When is insemination scheduled?
The development of the follicles in the ovaries is monitored by sonography. Usually we want to obtain several mature follicles, greater than 20 mm in size, with an endometrium (inner layer of the uterus) trilaminar 7 mm or greater in thickness. The time of ovulation is scheduled by administering an injection of hCG. IUI is performed one to two days after injection, depending on the follicular size. After hCG injection, aspirin or its derivatives (Advil, Aleve, Motrin, etc.) are not recommended as it inhibits the release of the egg from the ovary.
How is IUI performed?
Once collected, the semen sample is processed in the lab to concentrate the sperm and remove the seminal fluid (semen fluid components can cause severe cramps in the woman). This process can take up to 2 hours to complete. Culture medium with supplements is added to stimulate increased movement and fertilizing capacity of sperm.
IUI is done around the time the woman is ovulating. The IUI procedure is relatively simple and only takes a few minutes once the semen sample has been processed. Your doctor inserts a speculum into your vagina to visualize your cervix. A catheter (narrow tube) is inserted through the cervix into the uterus and the prepared sperm sample is slowly introduced. This procedure is usually painless, although some women may have mild cramping. Some women may experience spotting for a day or two after intrauterine insemination, due to cervical manipulation. After IUI, the patient should remain at rest for 15 minutes. That day, she can return to her normal activities, even having sex. Most patients are recommended to use vaginal progesterone starting several days after IUI. Pregnancy test is recommended 17 days after the IUI day.
Does it work?
Success varies depending on the underlying cause of infertility. IUI works best in patients with unexplained infertility, women with a cervix that limits the passage of sperm, and men who are unable to effectively ejaculate. For example, for unexplained infertility, the IUI pregnancy rate is twice as high than with no treatment.
IUI is not as effective for men who produce few sperm, little mobility or progression agility, or who have a low percentage of normal sperm. It does not help women who have affected fallopian tubes, moderate or severe endometriosis, or a history of pelvic infections. Other fertility treatments are better for these patients.
In general, inseminations are performed once a month during the most fertile day. Success rates depend on the use of fertility drugs, number of mature follicles developed, women’s age, and diagnosis of infertility, as well as other factors. The average patient takes 2.5 months to achieve a pregnancy.
Are there risks?
If a woman is taking fertility medications to increase the number of eggs when she has an IUI, her chance of getting pregnant is higher, but the incidence of multiple pregnancies (6% twins), or more is also higher. Having an IUI does not increase the risk of birth defects. The risk of congenital anomalies in all children is 2% to 4% whether conceived naturally or by intrauterine insemination and depends mainly on maternal age. The risk of developing an infection, ectopic pregnancy, or over-stimulation of the ovaries is very low. The incidence of miscarriages varies according to maternal age.
Laparoscopy
A laparoscopy is a minor surgical procedure frequently utilized to evaluate the pelvic organs of an infertile patient. A telescopic tube is introduced though the umbilicus (belly button) in order to see inside the peritoneal cavity. This procedure, which takes between 30 and 60 minutes, can be done in the Operating Room, on an outpatient basis. Laparoscopy allows us to evaluate a woman's anatomy without the need for exploratory surgery. Endometriosis, pelvic adhesions, anomalies of the fimbriae and tubal inability to retrieve the eggs after ovulation are all conditions that can only be diagnosed with precision through the laparoscope. Tube patency (permeability) is checked under direct visualization by means of a blue dye (methylene blue) introduced through the cervix and uterus. Operative laparoscopy allows us to carry out a limited number of surgical procedures, for example, fulguration of superficial endometriosis and lysis (division) of pelvic adhesions, to correct most pelvic conditions. Endoscopy photographs, video and DVD are made to document the case and instruct the patient.
Pelvic Reconstructive Surgery
During the last decade, advances in pelvic reconstructive microsurgery techniques have yielded unprecedented successes. The use of the microscope or surgical magnification, better sutures (being able to avoid chromic or non-absorbable sutures), special instruments that do not injure the tissues, the use of medication to prevent post-surgical adhesions, complete extirpation of diseased tissue and a perfect realignment of tissues have all resulted in a much better restoration of the anatomy, and a greater percentage of surgical pregnancies.
Reanastomosis, or the reconnection of the fallopian tubes in previously sterilized patients, is one of the most common and successful microsurgeries in more than 80% of selected cases.
Myomectomies are surgeries to remove myomas or fibroids in the womb. Myomas are nodes or usually benign tumors which appear very frequently in Latin American women. The procedure entails removing the myomas --without having to extirpate the uterus or womb-- to correct the cause of the problem and its symptoms, increasing the chances of gestating a pregnancy and/or preserving future fertility by avoiding a hysterectomy.
The aim of pelvic surgery is restoration of the anatomy. Previous pelvic surgeries such as those for ovarian cysts, for example, could have given rise to adhesions, scar tissue that bridges the natural divide between two organs and interferes with normal functioning. Advanced-stage endometriosis, accompanied by severe symptoms and/or endometrial cysts in the ovaries, can be corrected or mitigated by means of conservative endometriosis surgery.
Hysteroscopy
A hysteroscopy is a minor surgical procedure (done in the Operating Room, under general or local anesthesia) and it is similar to a cystoscopy. A small telescopic instrument is introduced through the cervix to visualize the uterine cavity. This way, the inside of the uterus can be checked, and certain uterine conditions can be diagnosed and operated on, under direct visualization.
The PRFC has also been a pioneer in offering treatments to help couples choose the sex of their next baby. The child's sex is determined by the sperm. Based on the different physical characteristics of the sperm, whether they are X or Y, it is possible to isolate a portion that is almost exclusively concentrated in either one or the other determinant of the baby's sex. With the rising cost of living today, many couples need to limit the number of children they raise, and many opt for sex selection to ensure they balance the composition of their family.
Only completely mature eggs can be injected. Usually, two out of every three injected eggs are fertilized and continue their cell division. The percentage of pregnancies achieved with the method is about 50%, almost the same as for standard laboratory insemination.
