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About Female Infertility
Current Diagnosis and Treatment of
Female Infertility: An Overview
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A couple is defined as being infertile after unsuccessfully attempting pregnancy for one year. In situations where a woman is near the end of her reproductive age-range, couples frequently are seeking help much sooner and rightly so, as the incidence of natural infertility increases with the advancement of the woman's age. While a conception is observed in approximately 30% of menstrual cycles in woman in their twenties, the incidence drops to about 15% per menstrual cycle in woman in their mid-thirties and reaches a low of less than 10% at age forty, dropping from there at a rate of 2-3% annually.
At the same time, the risk for chromosomal abnormalities and miscarriage related to chromosomal abnormalities of the offspring increases. This results in the recommendation of The American College of OB/GYN to undergo amniocentesis for all women over the age of thirty-five. The purpose of this test is to detect chromosomal abnormalities that are likely to significantly affect the baby's health, without however, being severe enough to produce a spontaneous abortion. In the United States infertility is observed in approximately one out of six couples and is estimated to affect six million women in this country alone.
Once the diagnosis of infertility has been established, being able to identify the causes for a couple's failure to conceive within a proper period of time is crucial to assure treatment success. Female infertility can be broken down into various categories which all require specific tests and evaluations.
PELVIC FACTOR -
Among the more frequent cause for women's infertility is the so-called pelvic factor. Pelvic factor infertility addresses the failure of the fallopian tubes to function normally either as a result of infection or adhesive disease and scar tissue generated through prior surgery, as well as various degrees and stages of endometriosis, an inflammatory condition resulting in disfiguration and alteration of a woman's pelvic anatomy, thereby affecting her reproductive function, not only from an inflammatory point of view, but from an anatomic point of view as well. Pelvic factor infertility also includes abnormalities of the uterus, either of congenital nature such as the subseptated uterus representing a congenital abnormality causing a significant reduction in the size of the uterine cavity or, for example, the presence of uterine fibroids in certain positions that can compromise the implantation and proper nutritional supply to an embryo. By far the most frequent reason for pelvic factor infertility is a sexually transmitted disease called chlamydial pelvic infection. The causing organism is called chlamydia trachomatis and unfortunately causes few to no systems that would be able to specifically indicate a potential ongoing infection to the infected woman. In advanced cases tubal obstruction, the closing off of the portion of the fallopian tube responsible for picking up the ovulated egg (fimbrea), can occur without symptoms such as fever, discharge, or pain. Approximately 50% of all women presenting with dilated and blocked fallopian tubes at time of a hysterosalpingogram (X-Ray to test the patency of the fallopian tubes) are entirely surprised by the diagnosis and are unable to identify any kind of pelvic pain or symptoms that would correlate with the obtained finding.
A similar fallopian tube condition can also be observed in women that were surgically treated for ruptured appendix as a result of chronic appendicitis. The incidence of tubal factor infertility after a ruptured acutely or chronically infected appendix is as high as 60%. Diagnostic steps to document the fallopian tube function and condition include the hysterosalpingogram, a hysterosonogram that can be performed in an office setting and does not require X-ray exposure as well as blood tests for chlamydia antibodies and cervical cultures for chlamydia and gonorrhea. If necessary the diagnostic use of laparoscopy may be helpful in properly diagnosing the extent of a suspected problem. Any woman battling with current episodes of genital herpes outbreaks, recurrent abnormal pap smears due to human papillomavirus contamination, or women with problems associated with the use of an intrauterine device should be alert towards the possibility of tubal factor infertility.
Treatment options include laparoscopic tuboplasty and lysis of tubal and ovarian adhesions as well as in-vitro fertilization, a treatment option that seems to become more and more attractive as success rates for this still quite expensive procedure continues to be on the rise. Based on data published by the Society for Assisted Reproductive Technologies after monitoring over 250 in-vitro fertilization clinics in this country, a woman in her twenties can easily expect a 35% delivery rate per procedure attempted with in-vitro fertilization. This statistical information makes a laparoscopic tuboplasty less and less attractive; in particular since it carries the risk of an ectopic pregnancy and may require up to a year for a pregnancy to occur in a woman treated with this procedure.
Another very frequent condition is pelvic endometriosis, defined as the presence of endometrial like tissue in the pelvic cavity (over the uterus, the pelvic sidewall, the fallopian tubes, the ovaries, the bladder wall and various ligaments connecting the uterus with other pelvic structures). Endometriosis is diagnosed in four stages, stage one being the least and stage four being the most extreme form of this progressive and probably genetically determined disease. As a result of internal bleeding episodes from endometriotic tissue implants at the time of the menstrual period, the affected woman's immune system is attempting to eradicate this atopic and improperly located tissue causing scarring, disfiguration of the pelvic anatomy and, by means of it's inflammatory agents, infertility based on an inference with a proper egg and sperm function. The diagnosis of endometriosis is difficult to establish correctly and properly without the use of laparoscopy. Any infertile woman with a family history of endometriosis should attempt to rule out this condition as soon as possible in the process of her workup. Unfortunately, blood tests are not successful in either screening or diagnosing this disease neither are menstrual cycles independent of pelvic pain. If laparoscopy is recommended to establish a proper diagnosis, it should always be combined with the potential for immediate treatment at time of the diagnosis, thereby avoiding an unnecessary procedure. Aggressive post-operative treatment may be necessary to accomplish pregnancy prior to recurrence of this condition, which appears to be Estrogen dependent and, if involving the ovaries in particular, can act destructive on the remaining pool of healthy oocytes of the affected patient. Extensive disease can often also be treated successfully in conjunction of a GnRH agronist causing the temporary occurrence of menopause and exerting its affect through the elimination of estrogen production for a three to six month time interval. Medical therapy however, may not be advisable to women in their late reproductive years as time is of the essence when attempting pregnancy. The inability to accomplish correction of anatomic abnormalities resulting from endometriosis makes a GnRH analog or other hormonal suppression therapy options including the long term use of injectable or oral progestins a less than ideal strategy.
A much rarer cause for pelvic factor infertility is the presence of uterine fibroids, which may block fallopian tubes or interfere with proper embryo implantation. Uterine fibroids are frequently observed in the American population and affect approximately one out of seven American women. Fortunately only a minority of these women are affected in their ability to conceive by these benign encapsulated muscle tumors. Hormonal suppression with GnRH analogues or surgical therapy to remove these structures and repair and reconstruct the uterus is the appropriate treatment of choice.
The by far least frequent pelvic factor condition is related to prior miscarriages, pregnancy terminations or complications with intrauterine devices defined as Asherman's syndrome or intrauterine scar tissue. This condition is frequently associated with reduced menstrual flow and consists essentially of the attachment of the front and back wall of the uterine cavity due to damage to the endometrial lining. Proper diagnosis is made either by hysterosalpingogram or diagnostic hysteroscopy/hysterosonogram. Treatment is often difficult and involves surgical repair attempts of the uterine cavity associated with high dose Estrogen therapy supplementation to regenerate the endometrium in the uterine cavity.
OVULATION FACTOR -
Approximately 40% of women presenting with infertility are unable to conceive because of lack of adequate ovulation. The term ovulation includes the maturation and release of an oocyte followed by provision of the proper hormonal environment to provide endometrial receptivity for implantation of an embryo. Ovulation occurs on a regular basis in women that menstruate at intervals between twenty-three and thirty-four days. Any menstrual cycle length below or above this range is frequently associated with anovulation. There are various conditions that can result in anovulation in women including polycystic ovarian disease, a congenital condition resulting in the inability of maturing oocytes, advanced reproductive age, hypo or hyperthyroidism, elevated Prolactin production, physical and emotional stress, the use of certain medications, in particular medications associated with an increase in Prolactin production and neurotransmitter alteration. Where causes for anovulation are chromosomal abnormalities such as those seen in Turner's syndrome (45 XO) as well as a hypothalamic disorder called Kallman's Syndrome, which is associated with the inability to smell and the inability to generate enough gonadotropin-releasing hormone to stimulate the pituitary follicle stimulating release. An even more unusual scenario for anovulation is a condition called Sheehan's Syndrome, which can be acquired after a traumatic delivery and consists of failure of the entire pituitary gland to function properly. In rare occasions advanced ovarian endometriosis, ovarian non-functional cysts, as well as over aggressive ovarian reconstructive surgery can result in secondary amenorrhea and anovulation.
The diagnostic tools to properly identify anovulation and its underlying causes consists of monitoring and proper documentation of a menstrual cycle and in the absence of a cyclic menstrual flow, the evaluation of the patient's hormone status including documentation of thyroid hormones, Prolactin level, pituitary stimulating hormones and a progesterone challenge test. Once maturation of a follicle is observed, ultrasound monitoring can be used to document egg release and corpus luteum formation as well as the changes associated with ovulation at the level of the endometrium. Progesterone levels obtained seven days after the LH surge which can be documented by the use of various urine test kits, is helpful identifying the quality of the luteal phase.
Correction of anovulation appears to be one of the most successful treatments in female infertility. In the absence of documented thyroid and Prolactin abnormalities a stimulating substance called Clomiphene Citrate is used to increase pituitary, FSH, and LH output. In more than 60% of patients undergoing treatment with this medication, ovulation can be temporarily restored. If unsuccessful, pituitary hormones available today in form of recombative FSH can be used either through intermuscular or subcutaneous injection to directly activate ovarian follicular activity. Observed conception rates for the use of Clomiphene are approximately 40% of users and for FSH medications approximately 60% of users.
In the area of side effects, the risk of multiple gestation needs to be addressed. Clomiphene Citrate seems to raise the multiple pregnancy risk to 5%, as opposed to 1% observed in the general non-fertile population. Fraternal twining in FSH users appears to be much more frequent and multiple pregnancies are observed at a rate of one in five (20%). Associated with the use of this drug is also a condition called ovarian hyperstimulation, which at times can result in significant fluid shifts between the vascular system and the so-called third space in the human body. This results in excess risk for coagulation, blood clot formation, kidney dysfunction as well as respiratory and nutritional complications. The use of this drug therefore needs to be monitored carefully and it should only be used by properly trained professionals. An additional concern with the use of these medications is the possible associated risk of the development of breast and ovarian malignancies. Although unresolved at this point, studies accumulate that suggest not only an association of an increase in ovarian cancer risk in women that have never carried a pregnancy to term but also in those women that have used excessive amounts of Clomiphene (more than twelve cycles of treatment). With the development of evermore successful techniques in the area of assisted reproduction the future will see a significant reduction in the need for the long-term use of these medications as pregnancy is being accomplished sooner.
A concern with the use of ovulation inducing medications appears to be its possible association with the induction of increased frequency of ovarian and breast malignancies. Although there is no clear clinical evidence at this point that the treatment with fertility medications increases cancer risk, the observation of a doubling of ovarian cancer risk in women that have never carried a pregnancy to term gives rise for concern. In addition, the extensive use of Clomiphene Citrate over more than twelve menstrual cycles also appears to increase cancer risk, addressing the need for more careful supervision, more complete, thorough evaluation prior to initiation of treatment and the use of the most sophisticated techniques to facilitate the occurrence of pregnancy within the shortest time possible. As we are progressing rapidly in improving the outcome with assisted reproduction technologies, a long-term use of fertility inducing medications will hopefully soon be a concern of the past.
CERVICAL FACTOR -
A small subgroup of women is infertile due to inability of the cervical anatomy or cervical mucus to provide a favorable environment for sperm to enter the uterine cavity and the fallopian tube. As the vaginal environment is generally hostile to sperm healthy sperm depend upon being able to enter the cervical mucus as soon as possible after ejaculation and this may not be possible in women that are unable to produce adequate amounts or quality of cervical mucus. Cervical mucus production is Estrogen dependent and a significant reduction in the quality and quantity of mucus is unfortunately seen in about one out of twenty patients undergoing ovulation treatment with Clomiphene Citrate. In this scenario ovulation may be induced however access of sperm will be prevented. Women having undergone therapy for abnormal pap smears due to dysplasia will often experience a reduction in the quality of the cervical mucus produced simply due to the depletion of cervical mucus producing cells as a result of the necessary surgery to remove dysplastic cells. Another scenario consists of the presence of sperm antibodies in the female reproductive system which are frequently seen in the cervical mucus and may attack various components of the sperm cell preventing it's access into the uterus and subsequently into the fallopian tube.
This problem can easily be identified by performing a post-coital test, which consists of the observation of cervical mucus under the microscope within twenty-four hours of having had intercourse at the time around ovulation. An abnormal post-coital in the presence of normal appearing cervical mucus may suggest antibody formation or a sperm problem. Absence of proper mucus in presence of optimal timing may suggest hormonal insensitivity of the cervical canal or depletion of cervical mucus producing cells. Occasionally chronic infection can be associated with such a condition as well.
If properly treated either by the use of proper antibiotics or through bypassing the cervical canal with the use of intrauterine insemination, this infertility factor can easily be overcome. A cervical factor is a classic indication for sperm washing with subsequent intrauterine insemination, a procedure performed on a regular basis in fertility practices across the nation and worldwide. As sperm are entered into the uterine cavity of the woman, the quality of the sperm preparation is paramount to assure tolerance and success. A well-equipped and staffed andrology laboratory is a prerequisite to the establishment of an insemination program. If inappropriately prepared, samples for intrauterine insemination can cause rejection reactions, vasovagal syncopes and infection. Proper monitoring of the post-sperm prep survival rate is also fundamental to assure success.
IMMUNOLOGIC FACTOR -
A small subgroup of women may suffer from infertility due to inability of their reproductive system to tolerate a fetal transplant. In order for gestation develop, a woman's immune system needs to develop tolerance to the fetus, which is not genetically identical with the mother. This phenomenon has been thoroughly addressed over the last few years and has resulted in the establishment of a subspecialty within reproductive medicine called Reproductive Immunology. While many of the associated factors appear to be hard to define and significant dispute over the validity of certain tests and treatment options, a variety of subspecialty laboratories are now investigating the presence of antiphospholipid antibodies, embryotoxic factors, lymphocytes called natural-killer cells, as well as increased compatibility in the human lymphocyte antigen type between husband and wife. Proposed, but by no means established treatment modalities include the use of blood thinners to prevent the mechanisms of hypercoagulation often associated with Antiphospholipid Antibody Syndrome as well as the use of immunoglobulins in the presence of abnormal natural-killer cell patterns and embryotoxic factors. Even the transfusion of the patient with the husband's lymphocytes to generate an immune tolerance pattern has been suggested. In summary, autoimmune intolerance is frequently associated with recurrent pregnancy losses but may also be involved in the prolonged unexplained infertility of select few couples.
AGE FACTOR -
Mention must be made regarding the issue of female reproductive age. As egg quality is known to deteriorate with advanced age, reproductive efficiency drops rapidly once a woman advances beyond the age of thirty-five. The determination of a Follicle Stimulating Hormone level in conjunction with an Estradiol level on cycle day two or three of any given menstrual cycle can be used as a guideline towards assessing reproductive potential. A significant elevation of the FSH level on day three is indicative of poor ovarian responsiveness and reduced egg quality. It has been associated with an increase in infertility and pregnancy loss. Improving circulation to the ovary, reducing exposure to toxins and increasing the body's ability to deal with metabolic waste occurring on a daily basis may stabilize or improve oocyte quality, just as it reduces the biologic age of any person. Although there are currently no established treatment regimes shown to be effective in preserving oocyte quality, the development of successful oocyte freezing techniques may enable woman to delay child bearing in the future, being able to use their cryopreserved (frozen) egg cells for successful reproduction in later years. Significant advances in freezing technologies and immature oocyte culture systems will be necessary to enter this protocol into clinically applicable treatments. Meanwhile, oocyte donation in conjunction with in-vitro fertilization is being used successfully to overcome this problem. Unfortunately, it can only be offered in conjunction with in-vitro fertilization and requires the woman to give up her genetic input in her offspring.
IN SUMMARY -
In summary, female infertility as it relates to anatomic, hormonal, autoimmune, cervical and age related factors has been researched extensively, can be identified if proper diagnostic tools are used in a adequate, timely fashion and treatment protocols are abundant, as well as successful, resulting in a high degree of success for women that decide to seek proper care when pregnancy appears to be elusive.
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