You are in: eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility InfertilityArticle Last Updated: Jan 23, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Jairo E Garcia, MD, Associate Professor, Director, Fertility Center and In Vitro Fertilization, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine Jairo E Garcia is a member of the following medical societies: American Society for Reproductive Medicine and Society for Gynecologic Investigation Coauthor(s): Lawrence M Nelson, MD, MBA, Head of Gynecologic Endocrinology Unit, Investigator, Developmental Endocrinology Branch, Section of Women's Health Research, National Institutes of Health; Edward E Wallach, MD, J Donald Woodruff Professor, Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine Editors: Robert K Zurawin, MD, Associate Professor, Director of Fellowship Programs, Minimally Invasive Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine; Chief of Gynecology, Texas Children's Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; A David Barnes, MD, PhD, Department of Obstetrics and Gynecology, Professor, University of Hawaii, Chubu Hospital; Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Assumption Community Hospital; Lee P Shulman, MD, Professor of Obstetrics and Gynecology, Feinberg School of Medicine, Department of Obstetrics and Gynecology, Northwestern University; Chief, Division of Reproductive Genetics, Prentice Women's Hospital, Northwestern Memorial Hospital Author and Editor Disclosure Synonyms and related keywords: infertility, lack of pregnancy, fertility, in vitro fertilization, IVF, intracytoplasmic sperm injection, ICSI, assisted reproductive technologies, ART, pelvic inflammatory disease, PID, endometriosis, sexually transmitted diseases, gonorrhea, chlamydia, STDs, cryopreservation, sperm donor, sperm morphology, sperm concentration, sperm quality, semen analysis, sperm washing, sperm evaluation, egg evaluation, egg quality, oocyte quality, egg donor, oocyte donor, gamete donation, oocyte donation, sperm donation, conception problems, pregnancy problems, pregnancy complications, pregnancy, normal infertile couple, NIC endometriosis, Rokitansky-Küster-Hauser syndrome, double vagina, absent vagina, absent uterus, uterine malformation, DES, diethylstilbestrol, sexual history, intrauterine fibroid, submucous fibroid, placental polyps, T-shaped uterus, tubal ligation, premature ovarian failure, luteal phase deficiency, luteal-phase deficiency, luteinized unruptured follicle syndrome, LUF syndrome, recurrent pregnancy loss, recurrent abortion, gamete intrafallopian transfer, gamete intra-fallopian transfer, GIFT, zygote intrafallopian transfer, zygote intra-fallopian transfer, ZIFT, partial zona dissection, PZD, subzonal sperm injection, SUZI, assisted hatching, AH, gestational carrier, surrogate carrier INTRODUCTIONSection 2 of 10
  Prevalence The most commonly accepted definition of the term infertility is the lack of pregnancy (regardless of cause) after 1 year of unprotected intercourse. Infertility affects approximately 15% of couples of reproductive age. Its prevalence has been stable during the past 50 years, although a shift in etiology and in the age of the patient population has occurred. Fertility is influenced by the moral attitudes of US society, in which sexual liberation and promiscuity have increased during the last 40 years, and by changing priorities among women. In developed countries, where family planning and professional career development are practiced, some women postpone childbearing until after age 30-40 years. Improvements in fertility treatment have made it possible for many patients with severe male-factor infertility to have a family. These new and advanced technologies include in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and other related procedures in Assisted Reproductive Technologies (ART). Fertility is defined as the capacity to reproduce or the state of being fertile. This term should be differentiated from fecundability, which is the probability of achieving a pregnancy each month, and fecundity, which is the ability to achieve a live birth within one menstrual cycle. The fecundability rate in the general population is rather constant and is approximately 0.22/mo (Maruani, 1983). The estimated fecundity rate is 0.15-0.18/mo, representing a cumulative pregnancy rate of 90%/y (Trussell, 1985). For excellent patient education resources, visit eMedicine's Pregnancy and Reproduction Center and Women's Health Center. Also, see eMedicine's patient education articles Infertility, In Vitro Fertilization, Amenorrhea, Menopause, Ectopic Pregnancy, and Miscarriage. ETIOLOGY OF INFERTILITYSection 3 of 10
The reproduction process requires the interaction and integrity of the female and male reproductive tracts, which allows for (1) the release of a normal preovulatory oocyte, (2) the production of adequate spermatozoa, (3) the normal transport of the gametes to the ampullary portion of the fallopian tubes (where fertilization occurs), and (4) the subsequent transport of the cleaving embryo up to the endometrial cavity for its normal implantation and further development. The origin of infertility is similarly due to male or female factors; the causes are multiple. Female factors account for 32% of infertility. Male factors account for 18.8% of infertility. Male and female factors combined cause 18.5% of fertility. The etiology is unknown in 11.1%, and other causes are identified in 5.6%. Those with an unknown etiology can also be categorized as a normal infertile couple (NIC), indicating that all findings from standard tests used to evaluate the patients are normal. In NICs, the actual cause for infertility cannot be detected because it may be at the oocyte/sperm level or it may be due to the quality of the embryo or to any disruption at the implantation site level. In the future, ascribing the mutation or the absence of a specific gene as the cause of infertility may be possible in this patient population. Other etiologic factors have been associated with an increased risk of infertility. These include pelvic inflammatory disease (PID); endometriosis; environmental and occupational factors; toxic effects related to tobacco, marijuana, or other drugs; exercise; inadequate diet associated with extreme weight loss or gain; and advanced age. Pelvic inflammatory disease PID has been associated with gonorrhea infection for more than a century (Brand, 1985). While gonorrhea still plays an important role in tubal disease, it has been surpassed by chlamydia. Westrom reported a 21% incidence of infertility in a group of Swedish women who were diagnosed with PID, which was confirmed by laparoscopy findings (Westrom, 1975). The rate of damage to the fallopian tubes increases with subsequent PID episodes, from 34% for the first episode to 54% in women with second and third episodes (Westrom, 1980). PID can be diagnosed clinically and confirmed by results from cervical culture and serologic antibody assays for gonorrhea and chlamydia (Moller, 1985; Tjiam, 1985; Robertson, 1987). In many instances, a patient never recalls having had an acute PID episode; however, years later, the incidental finding of tubal obstruction after hysterosalpingogram (HSG) or laparoscopy may be the only indication of previous PID. Endometriosis Endometriosis remains an enigmatic pathologic disease that affects women during their reproductive years. The incidence increases with patient age and low parity, and, although controversial, endometriosis appears to affect more patients in middle and high socioeconomic classes. The evolution of the disease is unpredictable. Pelvic pain and reproductive failure are the 2 major complaints of patients with endometriosis (Strathy, 1982; Balasch, 1996). Although a gene defect has not yet been identified for endometriosis, a genetic link seems probable based on the observation of chromosomal defects in endometriotic tissue and the observation of a 7-fold increased risk of endometriosis in patients with a family history of the disease (Simpson, 1980; Shin, 1997; Kennedy, 1998; Kosugi, 1999). Endometriosis lesions vary from microscopic to macroscopic. Classic endometriosis appears as black pigments, ie, powder-burn lesions that affect the surface of the peritoneum of the bladder, ovary, fallopian tubes, cul-de-sac, and bowel. Nonclassic endometriosis appears as nonpigments, ie, red, tan, white lesions or vesicles. The final diagnosis should be confirmed by demonstrating endometrial stroma and glands in biopsy tissue (Jansen, 1986; Martin, 1989). The incidence of endometriosis in primary and secondary infertility varies according to the population studied. Mahmood reported an incidence rate of 26% and 13%, respectively (Mahmood, 1991). Severe endometriosis with damage to the fallopian tubes and ovaries due to adhesions or the presence of endometriomas is an obvious cause of infertility. The hypothesis that minimal and mild endometriosis cause infertility is controversial. Several studies failed to prove an increased pregnancy rate after treatment or expectant therapy (Schenken, 1982; Seibel, 1982; Fedele and Parazzini, 1992; Fedele and Bianchi, Fertil Steril, 1992). Minimal and mild endometriosis is hypothesized to reduce fertility by the following mechanisms (Dmowski, 1981; Mathur, 1982; Muscato, 1982; Halme, 1984; Chacho, 1986; Gleicher, 1987; Mori, 1992; Hemmings, 1993; Akoum, 1995; Ryan, 1995; Garzetti, 1996; Harada, 1997; Braun, 1998; Koninckx, 1998):
Endometriosis has been associated with ovulatory disorders such as luteal phase deficiency (LPD), oligo-ovulation, and luteinized unruptured follicle (LUF) syndrome (Mahmood, 1991). Although pelvic pain appears to be a common symptom of endometriosis, in some patients, endometriosis is an incidental finding discovered during diagnostic laparoscopy for evaluation of infertility (Cornillie, 1990; Koninckx, 1991; Fedele, Obstet Gynecol, 1992; Vercellini, 1996). Environmental and occupational factors Concerns are currently increasing regarding the impact of environmental factors and subsequent repercussions on infertility. Published semen analysis reports from 1985 confirm a 20% decrease of sperm concentration compared with reports published in the 1960s (US Congress, 1985). Many other factors, such as excessive heat exposure, microwave radiation, ultrasonography, and other health hazards, are more controversial as real infertility-inducing factors (Thomas, 1990). Excessive radiation damages the germinal cells. Exposure to lead, other heavy metals, and pesticides has also been associated with male infertility (Buiatti, 1984; Bryant, 1989). Toxic effects related to tobacco, marijuana, and other drugs Smoking has been associated with infertility in both males and females (Baird, 1985; Howe, 1985; Mueller, 1989). In experimental animals, nicotine and polycyclic aromatic hydrocarbons block spermatogenesis and decrease testicular size. In women, tobacco alters the cervical mucus and the cilial epithelium and affects gamete transport (Stillman, 1986; Phipps, 1987). Marijuana and its metabolite, delta-9-tetrahydrocannabinol, inhibit the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thus inducing ovulatory disorders and LPD in women (Smith, 1987). Marijuana use affects males by decreasing the sperm count and the quality of the sperm. Heroin, cocaine, and crack cocaine use induces similar effects but places the user at increased risk for PID and HIV infection associated with sexual promiscuity. In women, the effects of alcohol are related more to severe consequences for the fetus. Nevertheless, chronic alcoholism is related to ovulatory disorders and, therefore, interferes with fertility. Alcohol use by males interferes with the synthesis of testosterone and has an impact on sperm concentration. Alcoholism may delay the sexual response and may be conducive to impotence. Exercise Exercise should be encouraged as part of normal activities. However, compulsive exercise is deleterious, especially for long-distance runners. Jogging stimulates the secretion of endorphins, and excessive secretion of endorphins interferes with the normal production of FSH and LH, in turn inducing ovulatory disorders and LPD, which accounts for lack of embryo implantation and first-trimester miscarriages (Baker, 1981; Green, 1986). In males, exercise has been associated with oligospermia. Inadequate diet associated with extreme weight loss or gain Obesity is becoming a major health issue in the United States. Obesity has an impact on infertility only when the female patient's weight reaches extremes. Although weight loss associated with anorexia nervosa or bulimia induces hypothalamic amenorrhea, a low FSH level, and low LH secretion, weight gain is tolerated better. Also, the disruption of the hypothalamic-pituitary-ovarian axis is affected in association with other endocrine disorders such as polycystic ovarian disease (PCOD), adrenal hyperplasia, and hypothyroidism. Advanced age The prevalence of infertility rises dramatically as age increases (US Congress, 1988). Furthermore, fertility decreases with marriage duration because of the decrease in the frequency of intercourse or the use of contraception. Studies report that among Mormons, fertility appears to be stable until age 36 years, declines slightly until age 40 years, and is followed by a sharp decline after age 42 years (Trussell, 1985; Menken, 1986). Similar conclusions can be drawn from the experience of IVF programs, as has been duplicated in multiple IVF studies worldwide. Chromosomal abnormalities and poor oocyte quality are 2 examples of causes of poor embryonic quality, low implantation rate, increased miscarriage, and low birth rates (Romeu, 1987). Analysis from donor oocyte programs in which the oocytes of younger patients (aged 21-30 y) are used has shown that the pregnancy rate in older recipients is comparable to the pregnancy rate of younger patients undergoing ART (Navot, 1994). Aging also affects male fertility. Testosterone levels decrease, gonadotropin levels increase, sperm concentration and semen volume change, and libido decreases. In addition, the incidence of birth defects increases. Age affects female fertility dramatically, but males are not affected as much; anecdotal reports exist of men fathering children when older than 80 years. GENERAL GUIDANCE ON EVALUATION OF INFERTILITYSection 4 of 10
Infertility is a problem that involves both partners equally. The consultation is incomplete if only the woman is evaluated. Anxiety is very common, and many couples seek consultation after a few months of unprotected intercourse. Diagnostic testing is unnecessary if the couple has not attempted to conceive for at least 1 year, unless they have a history of a male factor, endometriosis, a tubal factor, diethylstilbestrol (DES) exposure, PID, or pelvic surgery. A brief explanation of the physiology of reproduction and reassurance are enough to lessen the anxiety of the couple. History The patients (ie, the couple) should provide a copy of their previous medical records and should complete a medical history questionnaire to be submitted in advance of the initial consultation (see Image 105 for the Johns Hopkins "Husband and Wife Medical History Packet"). Obtain a detailed medical history regarding the type of infertility (primary or secondary) and its duration.
Physical A physical examination should be completed. Some health insurance carriers designate or include an obstetrician/gynecologist as a patient's primary care physician.
COMPREHENSIVE EVALUATION OF INFERTILITYSection 5 of 10
Evaluation of infertile couples should be organized and thorough. The findings must be discussed with the couple after completion of the history and physical examination. Diagnostic tests should progress from the simplest (eg, postcoital test [PCT], endometrial biopsy) to the more complex or to the one that implies a major risk to the patient (eg, laparoscopy). The couple will be stressed by their need to seek medical intervention; therefore, to relieve anxiety, emphasize that a complete infertility evaluation is performed according to the woman's menstrual cycle and may take up to 2 menstrual cycles before the factor(s) causing the infertility problem is found. Evaluation of the male partnerThe male partner must submit a semen sample for a comprehensive semen analysis. Previous paternity does not guarantee that his reproductive system has not been affected since the birth of his offspring. The comprehensive semen analysis must be performed in a certified andrology laboratory, and the semen sample, preferably, should be collected at the same andrology laboratory that will conduct the test. However, if the sample must be collected at home, it must be collected in a sterile plastic container and delivered to the andrology laboratory at body temperature not later than 30 minutes after ejaculation. Some patients cannot produce a semen sample through masturbation. Therefore, the sample can be collected through intercourse, using a special nonspermicidal condom provided by the andrology laboratory. To optimize results, the semen sample should be collected after a period of 3 days but no more than 5 days of sexual abstinence. Semen analysis The basic semen analysis assesses the characteristics of sperm concentration, motility, morphology, and viability. The World Health Organization's semen analysis parameters (with the variable and the corresponding reference range) are as follows (World Health Organization, 1992):
Morphology has become an important parameter to evaluate the quality of the sperm and to assess the fertilization capability. Kruger reported a new classification based on strict sperm morphology after fixing and staining the sperm (Kruger, 1986). Using the Kruger criteria, sperm morphology must be greater than 14% to be considered normal. Morphology of less than 4% is associated with severe infertility and is an indication for ART/ICSI. Specific biochemistry analyses relevant to the accessory sex gland functions can be performed using the semen sample. These include fructose from the seminal vesicles, zinc and acid phosphatase from the prostate gland, and alpha-glucosidases and carnitine from the epididymis (Zeneveld, 1990). Sperm agglutination indirectly indicates the presence of sperm antibodies. The immunobead test can be performed either directly on the sperm or indirectly on the sperm and blood. Surface antibodies against immunoglobulin A (IgA) or immunoglobulin G (IgG) may be present. The antibodies can be specific for the head or for the tail of the sperm (Clarke, 1985; Clarke, 1988; Barratt, 1992). IgA sperm antibodies interfere with the sperm-oocyte interaction and account for a lack of fertilization, whereas IgG sperm antibodies are more responsible for decreasing sperm motility. Sperm antibodies are associated with infection (ie, orchitis), testicular trauma, and a history of vasectomy. Interpretation of semen analysis Spermatogenesis takes approximately 72 days. Abnormal semen analysis results can be attributed to various unknown reasons (eg, short period of sexual abstinence, incomplete collection, poor sexual stimulus); therefore, repeating the semen analysis at least 1 month later is important before a diagnosis is made. Explaining to the patient the normal fluctuation that can occur between semen samples is also important. Avoid a hasty diagnosis that may create unnecessary anxiety for the couple. Azoospermia indicates absence of sperm that could be related to congenital absence or bilateral obstruction of the vas deferens or ejaculatory ducts, history of spermatogenesis arrest, Sertoli cell syndrome, or postvasectomy. Oligozoospermia indicates a concentration of fewer than 20 million sperm/mL and could be associated with ejaculatory dysfunction such as retrograde ejaculation. Asthenozoospermia indicates sperm motility of less than 50%. Extreme temperatures and delayed analysis after sperm collection are among the factors that decrease sperm motility. Teratospermia indicates an increased number of abnormal sperm morphology at the head, neck, or tail level. Hypospermia indicates a decrease of semen volume to less than 2 mL per ejaculation. Hyperspermia indicates an increase of sperm volume to more than 8 mL per ejaculation. Sperm function tests After ART, a proliferation of different sperm tests have been developed to evaluate and predict the sperm fecundability, including (1) the acrosome reaction test with fluorescent lectins or antibodies, (2) computer assessment of the sperm head, (3) computer motility assessment, (4) hemizona-binding assay, (5) hamster penetration test, and (6) human sperm-zona penetration assay (Margalioth, 1986; Franken and Burkman, 1989; Franken and Oehninger, 1989; Oehninger, 1989). Numerous publications describe the positive and negative aspects of these tests. The tests are diagnostic tools, and the results are subject to many variations in their interpretation, which render them of more academic interest than of practical therapeutic value. Evaluation of the female partnerSeveral congenital or acquired conditions affect female reproductive function. These conditions alter either the anatomy or the normal physiology of reproduction and may impair the transport of the gametes or embryo(s) and/or interfere with implantation and embryo/fetal development. A complete evaluation of the female reproductive tract must include cervical, uterine, endometrial, tubal, peritoneal, and ovarian factors. Cervical factors The uterine cervix plays a pivotal role in the transport and capacitation of the sperm after intercourse. The cervical factor accounts for 5-10% of infertility. Cervical mucus production, amount, and characteristics change according to the estrogen concentration during the late follicular phase. At the beginning of the menstrual cycle, cervical mucus is scanty, viscous, and very cellular. The mucus forms a netlike structure that does not allow the passage of sperm. Mucus secretion increases during the mid follicular phase and reaches its maximum approximately 24-48 hours before ovulation. The water and salt concentration increases, changing the physical characteristics of the mucus. It becomes thin, watery, alkaline, acellular, and elastic (spinnbarkheit) because of the increased concentration of sodium chloride, despite a fernlike pattern when the mucus is allowed to dry on a cover slide under the microscope (see Images 1-3). At this point, the mucus organizes itself, forming multiple microchannels so the spermatozoa can travel through. During this journey, the spermatozoa simultaneously undergo activation and capacitation (Overstreet, 1986). In addition, the mucus acts as a filter for abnormal spermatozoa and cellular debris present in the semen. Cervical-factor infertility refers to abnormalities of the mucus-sperm interaction. The PCT is also known as the Sims-Huhner test (Giner, 1974; Hull, 1982; Portuondo, 1982; Overstreet, 1986). The test consists of evaluating the amount of spermatozoa and its motility within the cervical mucus during the preovulatory period. The couple is asked to have intercourse, without the use of lubricants, 8-12 hours before the test. Although several articles have shown a higher sperm concentration 2-3 hours after intercourse, a longer interval of 8-12 hours provides the opportunity to evaluate sperm endurance. The mucus characteristics that determine a positive PCT test result are a volume of 0.3-1 mL, spinnbarkheit greater than 10 cm, a ferning pattern, occasional cellularity, and a sperm count of 10-20 per high-power field (eg, 45X motility forward progression). The timing of the PCT is crucial for the interpretation of results. If the PCT is scheduled too early or 24 hours after ovulation, a false-negative finding is the most likely result. Therefore, performing the test around the time of ovulation is recommended. If the patient has a 28-day menstrual cycle, the test should be performed on approximately menstrual cycle day 13-14. If the patient has menstrual irregularities, using a urinary LH kit to predict the preovulatory LH surge is advised in order to have a reliable PCT result. Changes in the basal body temperature (BBT) chart indicate ovulation. Although a BBT chart (see Image 59) taken during the menstrual cycle has been used for decades, the results from analysis are always retrospective and are misleading in approximately 20% of cases (Lenton, 1977). An abnormal PCT result may indicate (1) poor timing, (2) hostile cervical mucus related to cervicitis (eg, bacteria/yeast), (3) low pH, (4) sperm antibodies, (5) poor technique during intercourse (eg, premature ejaculation), (6) undiagnosed male factor infertility, and/or (7) anatomical defects (eg, due to DES exposure in utero, cervical cone). An abnormal PCT result must be repeated in subsequent cycles before a final diagnosis is made. Note that an abnormal PCT result does not preclude the possibility of a spontaneous pregnancy; therefore, be cautious to avoid a premature final diagnosis. Uterine factors The uterus is the final destination for the embryo and the place where the fetus develops until delivery. Therefore, uterine factors may be associated with primary infertility or with pregnancy wastage and premature delivery. Uterine factors can be congenital or acquired. They may affect the endometrium or the myometrium and are responsible for 2-5% of infertility cases. Other problems affect the development and function of the endometrium.
Endometrial factors The endometrial lining constantly responds to the different hormonal secretions that occur during the menstrual cycle or to the exogenous administration of estrogen and progesterone. In the 1950s, Novack and Noyes published their findings on the microscopic changes of the endometrium throughout the menstrual cycle and established the criteria for endometrial dating (Noyes, 1950). Jones first described the LPD and its association with recurrent pregnancy loss (RPL). LPD diagnosis is based on the lack of correlation between (1) endometrial development, diagnosed using premenstrual endometrial biopsy, and (2) the onset of the immediate menstrual cycle (Jones, 1949). To fulfill the diagnostic criteria, more than 2 days' difference must exist between the endometrial date and the beginning of the next menstrual period; furthermore, the same findings should be repeated in 2 consecutive menstrual cycles (Jones, 1977). The serum progesterone level is not a good parameter for diagnosing LPD unless several serum determinations are performed on different days throughout the luteal phase to calculate the total amount of progesterone under the curve (Jones, 1974). Images 55-58 show the endometrial changes during the menstrual cycle according to Novak and Noyes.
LPD is associated with ovulatory dysfunction that is related to the following 3 factors. The first is, at the time of ovulation, follicle size is small. The second is when the preovulatory LH surge is rather blunt. Although the LH level is high enough to induce resumption of myosis of the oocyte, it might not be enough to induce follicular rupture and normal corpus luteum function (Soules, 1989). The third is when follicle size development is normal (ie, 23-24 mm in diameter), the LH surge prior to ovulation is normal, and serum progesterone levels are normal. However, the progesterone receptor at the endometrium level may require more progesterone because of decreased sensitivity; therefore, these patients require a greater amount of progesterone to respond adequately (Saracoglu, 1985). Tubal factors The fallopian tubes play an important role in reproduction. After ovulation, the fimbriae pick up the oocyte from the peritoneal fluid that has accumulated in the cul-de-sac. The epithelial cilia transport the oocyte up to the ampulla. The capacitated spermatozoa are transported from the endometrium through the cornual section and advanced through the fallopian tube down into the ampulla, where fertilization occurs. The embryo initiates its early cleaving stages and is propelled upward to arrive at the endometrial cavity at the blastocyst stage (ie, 96-120 h after ovulation). Abnormalities or damage to the fallopian tube interferes with fertility and is responsible for abnormal implantation (eg, ectopic pregnancy). Obstruction of the distal end of the fallopian tubes accounts for accumulation of the normally secreted tubal fluid, creating distention of the tube with subsequent damage of the epithelial cilia. Other tubal factors associated with infertility are either congenital or acquired. Congenital absence of the fallopian tube(s) can be due to spontaneous torsion in utero followed by necrosis and reabsorption. Elective tubal ligation and salpingectomy are acquired causes. The 2 most frequent tests used for diagnosis of tubal pathology are HSG and laparoscopy (see Hysterosalpingogram and Laparoscopy). Peritoneal factors The uterus, ovaries, and fallopian tubes share the same space within the peritoneal cavity. The cul-de-sac is the reservoir for the peritoneal fluid that accumulates around the time of ovulation. The oocyte is released from the follicle and floats in the peritoneal fluid. The fimbriae of the fallopian tube pick up the oocyte within minutes after ovulation and transport it up to the ampullary portion, where fertilization occurs. This finely orchestrated mechanism is important for the normal reproductive process. Anatomical defects and/or physiologic dysfunctions of the peritoneal cavity, including infection, adhesions, and adnexal masses, account for infertility. PID, peritoneal adhesions secondary to previous pelvic surgery, endometriosis, and ovarian cyst rupture all compromise the motility in the fallopian tubes or produce blockage of the fimbriae with development of hydrosalpinx. Large myomas, pelvic masses, or blockage of the cul-de-sac interferes with the accumulation of peritoneal fluid and interferes with the normal oocyte pickup mechanism. Periovarian adhesions that encapsulate the ovary interfere with the normal oocyte release at ovulation, becoming a mechanical factor for infertility.
Ovarian factors Oogenesis occurs in the ovary from the first trimester of embryonic life and is completed by 28-30 weeks of gestation. By then, approximately 7 million oocytes are present. They are arrested at the prophase stage of the first meiosis division. Subsequently, the number of oocytes decreases because of a continuous process of atresia. At birth, the pool of oocytes is reduced to approximately 2 million. By menarche, approximately 500,000 oocytes are present. Those oocytes are used throughout the reproductive years until menopause. The ovulatory process is initiated once the hypothalamus-pituitary-ovarian axis matures and FSH and LH, under the regulation of gonadotropin-releasing hormone (GnRH), acquire their normal secretory patterns. From the cohort of follicles available each month, only a single oocyte is selected, establishes dominance, and develops to the preovulatory stage. During follicular development, the granulosa cells secrete increasing amounts of estradiol (E2), which, initially, through down-regulation, decreases the secretion of FSH. Later, through a positive feedback mechanism, E2 participates in the LH surge that triggers the ovulatory process, induces the resumption of meiosis by the oocyte, and stimulates the formation of the corpus luteum and subsequent progesterone secretion. Ovulatory dysfunction is defined as an alteration in the frequency and duration of the menstrual cycle. A normal menstrual cycle lasts 25-35 days, with an average of 28 days. Failure to ovulate is the most common ovulatory problem. Absence of ovulation can be caused by primary amenorrhea or premature menopause, indicative of the depletion of oocytes or absence of the ovaries. Oligomenorrhea (irregular or delayed ovulation) is related to dysfunction of the hypothalamus-pituitary-ovarian axis; the most common cause is PCOD (Goldzieher, 1981; Conway, 1989). Primary amenorrhea is the absence of a spontaneous menstrual period by age 16 years or after 3 years of pubarche and telarche (Frisch, 1971; Knobil, 1988). Primary amenorrhea is generally related to gonadal development failure, as in Turner syndrome, in which the karyotype 45,X indicates an absence of the X chromosome. These patients present with sexual infantilism associated with short stature, webbed neck, and cubitus valgus. Streak gonads replace their ovaries, but they have a small uterus and normal fallopian tubes and vagina. This condition is associated with elevation of FSH and LH in serum (menopausal stage) and low estrogen levels. Other chromosome abnormalities include 46,XX, which is associated with partial deletions of the short or long arm of one of the X chromosomes, and mosaicism (eg, X/XXX; X/XX/XXX; pure gonadal dysgenesis; 46,XX; 46,XY). Primary amenorrhea also occurs in patients with hypothalamic failure secondary to inadequate GnRH synthesis, neurotransmitter defects, or isolated gonadotropin insufficiency. Other entities associated with primary amenorrhea include congenital absence of the uterus, vagina, or hymen (cryptomenorrhea) and enzyme deficiencies such as 17-alpha hydroxylase deficiency and 17,20-desmolase deficiency. Secondary amenorrhea that is not related to a pregnancy is the absence of ovulation for more than 6 months. This condition is related to a severe dysfunction of the endocrine system and can be related to thyroid, adrenal, and pituitary disorders, including tumors. However, more frequently, secondary amenorrhea is related to premature ovarian failure.
Oligomenorrhea is a dysfunction of the hypothalamus-pituitary-ovarian axis and is the most common ovulatory disorder associated with infertility. Patients with this disorder present with a history of irregular menstrual cycles that fluctuate from 35 days to 2-5 months, sometimes associated with a history of dysfunctional uterine bleeding or prolonged periods of breakthrough bleeding. Patients may have symptoms of hyperandrogenism, acne, hirsutism, and baldness. Obesity is frequently associated and aggravates the prognosis. Although these patients are not sterile, their fertility is decreased, and the obstetrical outcome is poor because of an increased history of pregnancy losses. In patients with PCOD, the gonadotropin assay reveals a normal to slightly low FSH concentration and a slight or very elevated LH level. Prolactin, thyroid, and adrenal hormones can be elevated if a combination of glandular dysfunction (pluriglandular syndrome) is present. Pelvic ultrasonographic findings confirm the presence of enlarged ovaries with multiple small (<10 mm) follicles at the periphery of the ovarian cortex. During laparoscopy, the ovaries are enlarged with a rather smooth but thick cortex and an absence of corpora albicans (see Image 44). A monophasic BBT is associated with anovulatory cycles, although this is not a reliable finding in 20% of patients. A determination of serum progesterone level below 2 ng, an endometrial biopsy finding that shows a proliferative pattern, and pelvic ultrasonography results that show absence of a follicle and/or a corpus luteum are better criteria for diagnosing lack of ovulation. INFERTILITY TREATMENTSection 6 of 10
A consultation with the infertile couple once the evaluation has been completed is imperative. Outline a treatment plan according to the diagnosis, duration of infertility, and the woman's age. If pregnancy has not been established within a reasonable time, consider further evaluation or a different treatment plan. In many instances, patients are not well advised; therefore, their expectations are unrealistic, and the lack of success exacerbates their anxiety and frustration levels. Treatment of cervical factorsAn abnormal PCT result attributable to chronic cervicitis may be treated with antibiotics. Treatment of reduced secretion of cervical mucus due to destruction of the endocervical glands by previous cervical conization, freezing, or laser vaporization responds poorly to low-dose estrogen therapy. The easiest and most successful treatment is intrauterine insemination (IUI) (Te Velde, 1989). Similar treatments apply when the abnormal PCT result is related to oligospermia or hypospermia and to ejaculatory disorders such as impotence, hypospadias, or retrograde ejaculation (Moghissi, 1977; Nachtigall, 1979; Brassesco, 1988). Patients with azoospermia that is not amenable to IVF/ICSI treatment benefit from artificial insemination (AI) with donor sperm (Goss, 1975). AI can be performed by depositing the sperm at the cervical level (cervical insemination [CI]) (Nachtigall, 1979) or inside the endometrial cavity (IUI). CI has almost been abandoned because of its low success and has been relegated only to cases in which the sperm count is normal, such as in AI using donor sperm. For IUI, IVF, and ICSI procedures, the removal of certain components of the ejaculate (ie, seminal fluid, excess cellular debris, leukocytes, morphologically abnormal sperm) with the retention of the motile fraction of sperm is desirable. For most specimens, the greatest recovery of the motile portion results from separation via centrifugal filtration through a discontinuous density gradient system. However, for certain very poor specimens with low original concentrations of motile sperm, the use of the gradient system results in such a negligible recovery as to render it useless. The recourse for these specimens is to remove the seminal fluid by successive media washes. A small number of specimens have acceptable original concentrations of motile sperm but poor recoveries with the gradient system. These specimens benefit most from layering a washed pellet of sperm with nutrient media and allowing the motile fraction to swim up into the media before being separated (Kerin, 1989). After sperm preparation, the spermatozoa are enhanced in motility and become activated and ready to fertilize an oocyte. Currently, no reliable technique allows the separation of the X- and Y-bearing spermatozoa. IUI is performed during a natural cycle or after ovulation induction with CC or hMGs. The procedure is performed 30-34 hours after the spontaneous LH surge or 40-44 hours after the administration of 10,000 U of hCG (Silverberg, 1992). The sperm is delivered into the endometrial cavity using an IUI cannula. After injection of the sperm, the patient remains in the recumbent position for 10 minutes. Prophylactic antibiotics are not necessary unless a medical indication exists (eg, history of mitral valve prolapse). The average pregnancy rate achieved after a natural-cycle IUI is 8%. The rate increases to 10-12% after CC ovulation induction and to 12-15% per cycle after hMG/hCG ovulation induction. Of the successful pregnancies, 85% are achieved within the first 4 cycles of IUIs. Homologous insemination refers to the use of sperm from the patient's partner. Heterologous or therapeutic insemination (TI), formerly called artificial insemination by donor sperm, refers to the use of frozen sperm that has been quarantined for at least 6 months (Goss, 1975). Thereafter, the specimen is ready to use once the donor has undergone the necessary screening tests required by the tissue bank, the US Food and Drug Administration (FDA), and the American Society for Reproductive Medicine (ASRM) (American Fertility Society, 1991). The source of the sperm can be either anonymous or from a designated donor previously accepted by the infertile couple. A cumulative pregnancy rate of 80% is achieved during the first 6 cycles of TI. Treatment of uterine factorsUntil IVF became available, a patient with congenital absence of the uterus and vagina (Rokitansky-Küster-Hauser syndrome) had no chance to have a biologic child. Today, it is feasible by using a surrogate mother or gestational carrier. The treatment for patients with congenital absence of uterus and vagina consists of the creation of a neovagina for their normal sexual function (McIndoe, 1938). Once patients desire to have children, they proceed with stimulation of the ovaries, oocyte aspiration, and IVF, but the embryos are transferred to a gestational carrier (see In vitro fertilization). The treatment of uterine malformations depends on the severity of the problem. Fertility is not an issue for some patients affected by DES, and they remain undiagnosed until they have an abnormal Papanicolaou test (Pap smear) result. Those who do have fertility problems are treated according to the following guidelines (Kaufman, 1977; Haney, 1979; Barnes, 1980):
Unicornuate uterus A unicornuate uterus remains undetected unless fertility is compromised. Patients with this type of uterus can have a normal term of pregnancy. Most problems are related to premature labor and pregnancy loss. No treatment is available for this condition, and the patient eventually delivers a child after several pregnancy losses (DeCherney, 1986). In conjunction with a unicornuate uterus, 15% of patients are born without a kidney or with a pelvic kidney. Most patients are asymptotic; therefore, an intravenous pyelogram must be performed. Bicornuate uterus A bicornuate uterus causes only minimal problems with infertility (if any). A bicornuate uterus can be associated with a history of recurrent miscarriages, and its repair is indicated only if other etiologies for the miscarriage have been excluded (see Surgical intervention). Arcuate uterus In general, an arcuate uterus does not cause infertility. Whether it should be corrected in cases of primary infertility is debatable. Septate uterus The hypothesis that a uterine septum can cause infertility is controversial. It is difficult to advise surgery in cases of primary infertility. The basis for removal of the septum is related to the deficiency in blood supply in case the implantation of the embryo occurs at the septum level. Uterine anomalies can be corrected through operative hysteroscopy under general anesthesia or conscious sedation (DeCherney, 1986). Ideally, perform the procedure during the early follicular phase and under laparoscopic surveillance to decrease the risk of uterine perforation. Furthermore, the laparoscopy helps in the differential diagnosis between a septate uterus and a bicornuate uterus. A bicornuate uterus is characterized by the presence of an indentation at the fundus. The 2 techniques are the Strassman metroplasty and the Jones metroplasty. The Strassman metroplasty consists of performing an incision at the fundus of the uterus between both cornual areas and closing the defect with an anteroposterior suture. The Jones metroplasty consists of resecting the septum using an anteroposterior wedge incision and closing the defect in the same direction (Adamson, 1992; Jones, 1992; Khalifa, 1993) (see Images 83-84). Uterine synechiae Uterine synechiae are corrected using operative hysteroscopy. The surgery is performed during the early follicular phase. A good distention of the endometrial cavity is necessary to perform the procedure with minimal risk of uterine perforation. Once the defect is removed, leaving an intrauterine stent for 7 days is advisable to prevent a recurrence of adhesions. The patient should receive prophylactic antibiotics and uterine relaxants (eg, ibuprofen) during these 7 days to prevent infection and stent expulsion, respectively. The patient should be prescribed a high dose of E2 (5 mg qd for 21 d) followed by medroxyprogesterone (10 mg for 10 d). A postoperative HSG should be performed 2 months later. In many instances, more than one hysteroscopy is required for total resection. Endometrial polyps Endometrial polyps are removed through operative hysteroscopy associated with a dilatation and curettage, if necessary. An HSG follow-up procedure is not necessary. To prevent further polyp development associated with anovulation, the patient should have withdrawal bleeding at least every 6 weeks. Myoma treatment In general, small and asymptomatic myomas do not require treatment, but the patient should be periodically monitored. The fibroids should be treated if they are associated with hypermenorrhea or menometrorrhagia or if they are causes of infertility. Three modalities are used to treat myomas: medical treatment, surgical treatment, and embolization.
Treatment of endometrial factorsThe treatment of LPD should be oriented to treat the underlying factor; therefore, having a precise diagnosis of the ovulatory dysfunction is crucial. Patients who have a small follicle size at the time of ovulation should be treated with CC (50 mg qd for 5 d, starting on the second menstrual cycle d). Monitor follicular development using pelvic ultrasonography starting on the 10th menstrual cycle day and continue until the day of ovulation. Ideally, the follicle should be ovulated when the diameter is 23-24 mm. Blunt preovulatory LH surge is associated with LUF syndrome. Administer hCG (10,000 U) during a natural menstrual cycle when the follicle reaches 23-24 mm in diameter. Patients with normal follicle development, normal LH surge, and corpus luteum detected by ultrasonography, in whom the endometrial biopsy result still lags behind the normal date, should be treated with exogenous progesterone (eg, vaginal supp 50 mg qd), micronized progesterone (200 mg q6h), or oral progesterone (200 mg q8h). Start progesterone supplementation 48 hours after ovulation. Document the response to treatment of LPD by repeating the endometrial biopsy during the first cycle of treatment. The patient should continue the progesterone treatment for 2 weeks and should not discontinue the progesterone unless a pregnancy test result is negative. If the patient conceives during the treatment, continue progesterone until the 10th week of pregnancy. By this time, the placenta takes over the endocrine control of the pregnancy. Of the patients in whom the LPD treatment is adequate, 70% conceive during the first 6 months of treatment. If pregnancy has not occurred during that interim, further fertility evaluation is required to exclude other associated factors that interfere with the success of the treatment. Remember that other lethal factors account for RPL (eg, chromosome abnormalities), and the patient will have another miscarriage regardless of a corrected LPD. Treatment of tubal and peritoneal factorsThe treatment of tubal-factor infertility underwent major changes, especially during the last quarter of the century when microsurgery became available (Winston, Fertil Steril, 1980; Gomel, 1992). Tubal reconstruction was the only hope for those patients before ART became available. Because of the intimate relationship between the fallopian tubes and the other pelvic organs and because, in the great majority of the cases, peritoneal pathology involves tubal pathology, the treatments of these factors are discussed together. Tubal and peritoneal factor infertility treatment requires a good surgeon who is skilled in currently available techniques (Rock, 1984). The patient's age and the severity of the tubal pathology play important roles in the selection of patients, as do any other infertility issues such as the presence of endometriosis and severe pelvic adhesions. Before surgery, review the HSG films and the results of previous laparoscopy, if available, to decide on the type of surgical technique that is required and to explain to the patient the expected degree of success and risks involved with the procedure. Tubal obstruction and lysis of adhesions can be corrected through laparotomy, operative laparoscopy, and, in special circumstances, through operative hysteroscopy and tubal cannulation. Laparotomy is indicated in patients with severe pelvic adhesions that compromise the bowel, ovaries, and tubes, with obliteration of the cul-de-sac (Ismajovich, 1984). The aim of the procedure is to correct what is necessary to allow the normal transport of the gametes; complete restoration of the anatomy is not intended (Caspi, 1979). Lysis of adhesions should be meticulous, using hydrodissection and fine instruments. Avoid blunt dissection. Constant irrigation with Ringer lactate solution and heparin prevents fibrin formation. Meticulous hemostasis is imperative (Rock, 1978; Jones, 1983; Murphy, 1992). Operative laparoscopy was reintroduced into the surgical armamentarium in the 1950s; however, in the 1970s, Semm developed different procedures and operative instruments that currently allow for the outpatient surgical treatment of multiple tuboperitoneal pathologies (Semm, 1979). Electrocautery, endocoagulation, lasers, and ultrasonography scalpels facilitate the performance of operations that otherwise required a laparotomy a few years ago. Operative hysteroscopy associated with tubal cannulation is helpful to treat cornual obstruction. Treat fimbrial phimosis and periadnexal disease with laparoscopy (Gomel, 1977; Mettler, 1979; Daniel, 1984; Donnez, 1987; Schlaff, 1991). The pregnancy rate after salpingolysis is 50-60% during the first year after treatment. Fimbrioplasty for fimbria agglutination or phimosis without destruction of the cilial epithelium is equally successful. The incidence rate of ectopic pregnancy after surgery is in the range of 5%. Treatment of hydrosalpinx (distal tubal obstruction) with salpingostomy can be performed through microsurgery or operative laparoscopy. No difference in the pregnancy rate occurs if a skillful microsurgeon or laparoscopist performs the salpingostomy. The success of the procedure is related to the diameter of the hydrosalpinx and to the damage to the cilial epithelium. If the cilial epithelium has been destroyed, the outcome of the procedure is poor, and it is better to perform a salpingectomy in preparation for future IVF. The pregnancy rate fluctuates from 20-35%, and the expected ectopic pregnancy rate is as high as 20%. Treatment of cornual obstruction (proximal) should start by confirming the diagnosis. In many cases, cornual obstruction diagnosed based on HSG findings can be a false obstruction caused by a simple cornual spasm. Before performing a tubocornual anastomosis, the patient must have a diagnostic laparoscopy associated with tubal cannulation by hysteroscopy (Confino, 1988; Novy, 1988; Confino, 1990). If one tube remains open, anastomosis is not needed because pregnancy can be achieved in 50% of cases. The success rate of tubocornual anastomosis fluctuates from 20-58%. The ectopic pregnancy rate is 5-7%. If the obstruction is caused by salpingitis isthmica nodosa or fibrosis, the best results are achieved through IVF (Schoysman, 1984). Surgical preparation for IVF The surgeon should be as conservative as possible but should bear in mind that the patient is better served with a single well-functioning fallopian tube than 2 defective tubes, which elicits an increased risk for ectopic pregnancy or recurrence of pelvic adhesions. If the fallopian tubes are beyond repair, bilateral salpingectomy with destruction of the cornual area is recommended in preparation for IVF. Tubal obstruction due to elective sterilization is better repaired with microsurgery, although the modern tendency is to perform the anastomosis using operative laparoscopy (Winston, Clin Obstet Gynecol, 1980; Jansen, 1986; Rock, 1987). In either event, knowing in advance what type of tubal ligation technique was used is important. Unfortunately, tubal cauterization destroys a great deal of tissue, so that the amount of fallopian tube remaining is often not long enough to facilitate a successful reanastomosis. Before anastomosis, evaluate the patient using HSG and laparoscopy findings to measure how far proximal and distal fragments of the fallopian tubes remain from the tubal ligation. To have a successful reanastomosis, the final tube should measure at least 4.5 cm. If fimbriectomy was performed, no treatment is available other than IVF. The best candidates for tubal reanastomosis are patients who had tubal ligation by the method of fallopian ring, Hulka clip, or Pomeroy (Rock, 1987). The pregnancy rate following a tubal reanastomosis performed by a skillful surgeon fluctuates from 70-80%. The ectopic pregnancy rate is approximately 7%. Treatment of endometriosis Endometriosis treatment may be divided according to the severity of the disease and patient needs. Four alternatives are currently available to treat endometriosis: expectant therapy, surgical intervention, medical treatment, and combined therapy.
Treatment of ovarian factorsOvulation induction is the treatment for infertile patients who still have oocytes within the ovaries but in whom a dysfunction of the hypothalamic-pituitary-ovarian axis exists. The ovulation induction agents used include CC, hMG, hCG, recombinant FSH, and recombinant LH. Clomiphene citrate (Clomid, Serophene) The chemical formula for CC is 2-[p-(2-chloro-1,2-difhenylvinyl) phenoxy] triethylamine dihydrogen citrate. CC is a nonsteroidal estrogen capable of interacting with estrogen receptor–binding proteins in a manner similar to estrogen but in a more prolonged way (Clark, 1974; Clark 1981). Therefore, CC behaves similar to an antiestrogen. CC has been in clinical use since the early 1960s. Its mechanism of action is still not well understood, but it competes for the estrogen receptor at the hypothalamus, pituitary, and ovarian levels. Because of the action at the estrogen-receptor level within the hypothalamus, CC alleviates the negative feedback effect exerted by endogenous estrogens (Tobias, 1981; Adashi, 1984; Kokia, 1990). As a result, CC normalizes the GnRH release; therefore, the secretion of FSH and LH is capable of normalized follicular recruitment, selection, and development to reestablish the normal process of ovulation (Tobias, 1981; Miyake, 1983). The standard dose of CC is 50 mg PO qd for 5 days, starting on the fifth menstrual cycle day or after progestin-induced bleeding. As an antiestrogen, CC requires that the patient have some circulating estrogen levels; otherwise, the patient will not respond to the treatment. The CC response is monitored using pelvic ultrasonography starting on the 12th menstrual cycle day. The follicle should develop to a diameter of 23-24 mm before a spontaneous LH surge occurs. BBT can be used to observe the thermogenic shift (temperature rises 0.5°F above the basal level) induced by the early secretion of progesterone. The only disadvantage with BBT is that in many instances, the shift does not occur in a clear way, and the patient misses the time of ovulation. While BBT is an inexpensive way to monitor ovulation, it is often impractical. Urinary monitoring of the LH surge (eg, with an LH Predictor Kit) can be a substitute for BBT. The patient should start monitoring the urinary LH secretion daily starting on the 12th menstrual cycle day. Ovulation usually occurs within the 32-40 hours after the indicative color change. Serum LH determination is more precise, especially when performed in combination with pelvic ultrasonography. A postovulatory ultrasonography should be performed during the first CC cycle to exclude the presence of LUF syndrome. Because of the antiestrogenic effect, CC may desiccate the cervical mucus, creating an iatrogenic cervical factor that can be responsible for the lack of pregnancy in a patient who has otherwise ovulated (Shirai, 1972). Therefore, a PCT must be performed during the first CC cycle and every time the doses of CC are increased. Other adverse effects associated with CC are hot flashes, scotomas, dryness of the vagina, headache, and ovarian hyperstimulation, which, although rare, has been reported in patients who are sensitive to CC (Southam, 1962; Scommegna, 1969). Whether the use of CC increases the risk of ovarian cancer is unknown, although 2 articles illustrate a potential risk (Rossing, 1994). Other authorities disagree with this assumption. The principal indications for CC use are in patients with oligomenorrhea, especially PCOD, and for patients with slight menstrual irregularities. CC is indicated in the treatment of patients with LPD due to small-size follicle development (van Hall, 1969; Garcia, 1977). Its use has been extended to ART. The use of CC is contraindicated in cases of ovarian cyst, pregnancy, and liver disease. Its use is controversial in patients with a history of breast cancer. Human menopause gonadotropins Crowe discovered that the gonads were under the control of the anterior hypophysis (Crowe, 1966). Zondek and Aschheim discovered that FSH and LH were responsible for the development of the gonads in immature animals and confirmed Crowe's work (Mettler, 1979; Daniel, 1984; Schlaff, 1991). In the 1930s, ovulation induction was attempted by using gonadotropins from a mare, but its use was discontinued because of the development of antibodies (Cole, 1930; Leethem, 1948). Borth et al demonstrated the effect of FSH and LH extracted from menopausal urine (Borth, Experientia, 1954; Borth, Human Pituitary Gonadotropins, 1961). Gemzell reported the first ovulation induction using human pituitary gonadotropin in 1958, and the first pregnancy was reported in 1960 (Gemzell 1958; Gemzell, 1960). Lunenfeld reported preliminary results using hMG; however, in 1963, it was definitely established as a real ovulation induction agent (Lunenfeld, 1963; Domini, 1964; Spadoni, 1974). hMG (Repronex) contains 75 U of FSH and 75 U of LH per mL, although the concentration may vary among batches (ranges from FSH at 60-90 U and LH at 60-120 U). In the 1980s, a pure form of FSH became available. Bravelle contains 75 U of FSH. The new generations of available gonadotropins are produced by genetically engineered mammalian cells (ie, Chinese hamster ovary cells), in which the gene coding for the alpha and beta FSH subunits has been inserted (Gonal F and Follistim) (Devroey, 1992). Recombinant LH is currently undergoing clinical trials. The administration of hMG and its derivatives should be under the direct supervision of a reproductive endocrinologist. An ultrasonography unit and an endocrine laboratory capable of performing daily determinations of E2, FSH, and LH are necessary (Cabau, 1981; Garcia, 1983; Hackeloer, 1984; Lequin, 1986). Multiple adverse effects and complications may occur during the use of the gonadotropins, to include (1) multiple pregnancy (24-33%); (2) ectopic pregnancy (5-8%); (3) miscarriages (15-21%); (4) ovarian torsion and rupture; and (5) ovarian hyperstimulation syndrome (OHSS), which is the most severe (Schenker, 1979; Brown, 1986). Whittemore et al, using a large combined data set derived from case-controlled studies in the United States, showed that the increase of ovarian cancer associated with infertility might be due to the use of fertility drugs (Whittemore, 1992). OHSS is an iatrogenic condition that occurs in patients undergoing ovulation induction with hMG or controlled ovarian hyperstimulation (COH) for ART. The incidence rate fluctuates from 0.1-2%. The pathophysiology of the disease is not well understood, but a massive extravascular accumulation of fluid occurs that is associated with a severe depletion of the intravascular volume responsible for dehydration, hemoconcentration, and electrolyte imbalance (ie, hyponatremia, hyperkalemia) (Tollan, 1990). OHSS can be mild, moderate, or severe (Golan, 1989). Mild OHSS is characterized by ovarian enlargement (up to 5 cm in diameter), minimal ascites, and weight gain of less than 10 lb. Moderate OHSS is characterized by ovarian enlargement (5-12 cm in diameter) moderate ascites, nausea, vomiting, abdominal discomfort, and weight gain greater than 10 lb. Severe OHSS is characterized by easily palpable ovaries, severe ascites, nausea, vomiting, diarrhea, shortness of breath, hydrothorax, peripheral edema, oliguria, hemoconcentration (eg, hematocrit level >48% and hemoglobin level >16 g), and creatinine level greater 1.6 mg/dL. Renal failure and thrombosis can occur if the patient is not treated correctly (Whelan, 2000). Some patients have a greater risk of developing OHSS. They usually ar |