Gynecology_Novak

Gynecology_Novak. Figure 32.1 Diagnostic and treatment algorithm: infertility. HSG, hysterosalpingography. (From Yao M. Clinical management of infertility. Washington, DC: The Advisory Board: 2000, with permission.) Factors from either or both partners may contribute to difficulties in conceiving; therefore, it is important to consider all possible diagnoses before pursuing invasive treatments. The relative prevalence of the different causes of infertility varies widely among patient populations (Table 32.1). In many cases, no specific cause is detected despite a thorough evaluation, and the couple’s infertility is categorized as unexplained. Very few couples have absolute infertility, which can result from congenital or acquired irreversible loss of functional gametes in either partner or the absence of reproductive structures in either partner. In these specific instances, couples should be counseled regarding their options for adoption, use of donor gametes, or surrogacy.


Gynecology_Novak

Gynecology_Novak. Brain imaging (MRI is the gold standard) to exclude  Pituitary microadenoma  Pituitary macroadenoma  Other abnormal brain mass Hypothyroidism  Exclude secondary causes  Treat condition  Supplement with thyroid hormone if indicated  Spontaneous ovulation will occur when thyroid function normalizes  Treat underlying condition  When prolactin normalizes, spontaneous ovulation should occur Anovulation Normal or high day 3 FSH and LH Ovarian disorders (see Figure 30.3) Low LH, FSH, TSH, GH, ACTH High serum prolactin levels Abnormal TSH or T4Low FSH, LH, E2 Hypothalmic disorders Thyroid disease Hyperprolactinemia Panhypopituitarism Assess and treat condition Repeat test to exclude false positive Elevated prolactin If a pituatary microadenoma is diagnosed  Bromocriptine or cabergoline to normalize prolactin level  Spontaneous ovulation should occur when prolactin is normal Anorexia  Medical and psychiatric assessment  Treat condition  Aim to increase BMI to allow spontaneous


Gynecology_Novak

Gynecology_Novak. to normalize prolactin level  Spontaneous ovulation should occur when prolactin is normal Anorexia  Medical and psychiatric assessment  Treat condition  Aim to increase BMI to allow spontaneous ovulation  If female athlete triad, assess bone density, diet, caloric in take Hypogonadotropic hypogonadism  Congenital or acquired  Brain imaging Hyperthyroidism  Evaluate cause  Treat condition Ovulation induction  Pulsalite GnRH-agonist  Induce FSH and LH release Ovulation induction  FSH intrauterine insemination  FSH timed intercourse If no spontaneous ovulation, exclude irreversible damage to pituitary


Gynecology_Novak

Gynecology_Novak. Figure 32.2 Diagnostic and treatment algorithm: anovulation. FSH, follicle-stimulating hormone; LH, luteinizing hormone; E2, estradiol; TSH, thyroid-stimulating hormone; T4, thyroxine; GH, growth hormone; ACTH, adrenocorticotropic hormone; BMI, body mass index; MRI, magnetic resonance imaging; GnRH, gonadotropin-releasing hormone. (From Yao M. Clinical management of infertility. Washington, DC: The Advisory Board: 2000, with permission.)  Associated with increased age, decreased egg quality  Predicts decreased chance of successful treatment  Associated with increased risk of aneupliody and miscarriage Ovarian disorders  Infrequent menses hot flashes  Signs of decreased estrogenization  High FSH, LH (postmenopausal range)  High day 3 FSH  Abnormal CCCT  Advanced age Premature ovarian failure Decreased ovarian reserve Assess for and treat secondary or associated medical problems Premature ovarian failure is usually irreversible, but spontaneous sporadic ovulation and pregnancy


Gynecology_Novak

Gynecology_Novak. failure Decreased ovarian reserve Assess for and treat secondary or associated medical problems Premature ovarian failure is usually irreversible, but spontaneous sporadic ovulation and pregnancy have been reported  ART  Donor egg in vitro fertilization embryo transfer  Discuss adoption  May have brief trials of superovulation-intrauterine insemination or in vitro fertilization Figure 32.3 Diagnostic and treatment algorithm: ovarian disorders. FSH, follicle-stimulating hormone; LH, luteinizing hor-mone; CCCT, clomiphene citrate challenge test ART, assisted reproductive technology. (From Yao M. Clinical management of infertility. Washington, DC: The Advisory Board: 2000, with permission.) in the next section. Women who smoke need twice the number of IVF cycles to conceive as nonsmokers, but the effect of alcohol on fertility is less clear (18).


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Gynecology_Novak. Table 32.1 Causes of Infertility Relative prevalence of the etiologies of infertility (%)


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Gynecology_Novak. Spermatogenesis The male reproductive tract consists of the testis, epididymis, vas deferens, prostate, seminal vesicles, ejaculatory duct, bulbourethral glands, and urethra. Gonadotropinresponsive cells in the testes include Leydig cells (the site of androgen synthesis) and Sertoli cells, which line the seminiferous tubules (the site of spermatogenesis). The pituitary gland secretes luteinizing hormone (LH), which stimulates the synthesis and secretion of testosterone by the Leydig cells, and follicle-stimulating hormone (FSH), which acts with testosterone on the Sertoli cells to stimulate spermatogenesis (26). In humans, a new cohort of spermatogonia enter the maturation process every 16 days, and the development from spermatogonia stem cells to the mature sperm cells takes about 75 days (27). Spermatogonia undergo mitotic division to give rise to spermatocytes. These diploid spermatocytes subsequently undergo meiosis to produce haploid spermatids, which contain 23 (rather than 46)


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Gynecology_Novak. (27). Spermatogonia undergo mitotic division to give rise to spermatocytes. These diploid spermatocytes subsequently undergo meiosis to produce haploid spermatids, which contain 23 (rather than 46) chromosomes (26). Maturation of spermatids is called spermiogenesis and involves condensation of the nucleus, formation of the ﬂagellum, and the formation of the acrosome (a structure derived from the Golgi complex covering the tip or head of the sperm nucleus) (28). The resultant spermatozoa are released into the seminiferous tubule lumen and then enter the epididymis, where they continue to mature and become progressively more motile during the 2 to 6 days that are required to traverse this tortuous structure and reach the vas deferens (29).


Gynecology_Novak

Gynecology_Novak. Sperm Transport During ejaculation, mature spermatozoa are released from the vas deferens along with ﬂuid from the prostate, seminal vesicles, and bulbourethral glands. The released semen is a gelatinous mixture of spermatozoa and seminal plasma; however, this thins out 20 to 30 minutes after ejaculation. This process, called liquefaction, is the direct result of proteolytic enzymes within the prostatic ﬂuid (30). Following ejaculation, the released spermatozoa must undergo capacitation to become competent to fertilize the oocyte. Capacitation occurs within the cervical mucus and involves removal of inhibitory mediators such as cholesterol from the sperm surface, tyrosine phosphorylation, and calcium ion inﬂux, all of which allow the sperm to recognize additional fertilization cues during travel through the female reproductive tract. When the sperm reach the tubal isthmus they are slowly released into the ampulla, further reducing the number of sperm that reach the oocyte (31). Sperm


Gynecology_Novak

Gynecology_Novak. travel through the female reproductive tract. When the sperm reach the tubal isthmus they are slowly released into the ampulla, further reducing the number of sperm that reach the oocyte (31). Sperm transport from the posterior vaginal fornix to the fallopian tubes occurs within 2 minutes during the follicular phase of the menstrual cycle (32).


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Gynecology_Novak. Fertilization As the capacitated sperm near and pass through cumulus cells surrounding the oocyte, hydrolytic enzymes are released from the acrosome via exocytosis in a process called the acrosome reaction. Both capacitation and the acrosome reaction can be induced in vitro (28,31). Following the acrosome reaction, the sperm binds to and penetrates the zona pellucida (the extracellular coat surrounding the oocyte). This allows the sperm to fuse with the plasma membrane of the oocyte, an event that promotes changes in the oocyte and prevent entry by additional sperm (31). As the first sperm penetrates the zona pellucida, cortical granules are released (the cortical reaction) from the oocyte into the perivitelline space. This stops the oocyte’s zona pellucida from binding new sperm and inhibits penetration by previously bound sperm, further reducing the possibility of polyspermy (33). Table 32.2 Drugs that Can Impair Male Fertility


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Gynecology_Novak. Table 32.2 Drugs that Can Impair Male Fertility Erectile dysfunction β-blockers, thiazide diuretics, metoclopramide Drugs of misuse Anabolic steroids, cannabis, heroin, cocaine From Hirsh A. Male infertility. BMJ 2003;327:669–672, with permission.


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Gynecology_Novak. Sperm Sensitivity to Toxins Decreased sperm concentration and motility have been noted in areas of the United States with heavy agriculture and pesticide use, but occupational exposures have not been linked to infertility (24,34). Higher intake of food containing soy is associated with lower sperm concentrations (35). Alcoholism negatively affects all semen analysis parameters, and either smoked or chewed tobacco is associated with decreased density and motility (36–39). Marijuana inhibits motility and the acrosome reaction in vitro, and cocaine inhibits sperm motility and is associated with male infertility (40–42). Certain drugs may reduce sperm numbers or function or may cause ejaculatory dysfunction (Table 32.2). Vaginal lubricants such as Astroglide, KY Jelly, saliva, and olive oil inhibit sperm motility in vitro, while no adverse effects are seen with hydroxyethylcellulose (Pre-Seed), mineral oil, or canola oil (32).


Gynecology_Novak

Gynecology_Novak. Semen Analysis The basic semen analysis measures semen volume, sperm concentration, sperm motility, and sperm morphology (30). Recently revised, the normal values suggested by the World Health Organization (WHO) in 2010 are listed along with the previously published guidelines in Table 32.3 (30,43). Both criteria were developed using fertile men whose semen parameters were in the lowest fifth percentile of the group studied, but values above the reference ranges do not guarantee male fertility. Furthermore, since infertile men were not used to develop the criteria, values below the cutoffs may not necessarily indicate infertility (30). However, significant deviations from the reference limits are generally classified as male factor infertility (44). Given regional differences in semen quality and between laboratories, laboratories are encouraged to develop their own reference ranges. Typically, semen is assessed manually, but computer-aided sperm analysis (CASA) may be used.


Gynecology_Novak

Gynecology_Novak. semen quality and between laboratories, laboratories are encouraged to develop their own reference ranges. Typically, semen is assessed manually, but computer-aided sperm analysis (CASA) may be used. Limitations of CASA include a lack of standardization among instruments, an inability to differentiate intact from nonintact sperm, possible bias from artifacts during preparation, and a paucity of studies on fertility outcomes in large populations (30).


Gynecology_Novak

Gynecology_Novak. Abstinence Abstinence of a minimum of 2 to a maximum of 7 days usually is recommended prior to the semen analysis, but the optimal duration is unknown (30). The epididymis stores the equivalent of three ejaculations (29). With prolonged abstinence, sperm overﬂow into the urethra and are ﬂushed out into the urine (30). A study of men attending an infertility clinic found that the total motile sperm count and normal morphology decreased after 10 days’ abstinence in normozoospermic men but after 5 days’ abstinence in oligozoospermic men (45). There are conﬂicting reports regarding the impact of shorter abstinence of 1 or 2 days on semen parameters (45,46), but one study suggested intrauterine insemination success rates might be improved by shortening abstinence times prior to specimen collection (46).


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Gynecology_Novak. Specimen Collection The specimen should be obtained by masturbation and collected in a clean container kept at ambient temperature (30). The patient should report any loss of the specimen, particularly the first portion of the ejaculate, which contains the highest sperm concentration. Collection may be performed either at home or in a private room near the laboratory. The sample should be taken to the laboratory within 30 minutes to 1 hour of collection to prevent dehydration and degradation. If masturbation into a container is not possible, condoms specially designed for semen analysis should be used rather than latex condoms, which are toxic to sperm. Intercourse to collect the sample is discouraged because of the risk of contamination. Even when the specimen is obtained under optimal circumstances, interpretation of the results of the semen analysis is complicated by variability within the same individual and Table 32.3 Semen Analysis Terminology and Normal Values


Gynecology_Novak

Gynecology_Novak. Table 32.3 Semen Analysis Terminology and Normal Values Oligozoospermia Reduced sperm numbers Mild to moderate: 5–20 million/mL Severe: <5 million/mL Teratozoospermia Increased abnormal forms of sperm Necrozoospermia All sperm are nonviable or nonmotile Normal Semen Analysis: World Health Organization Volume 2mL ≥1.5 mL Immunobead or mixed antiglobulin <10% coated with antibodies <50% reaction test Terminology from Hirsh A. Male infertility. BMJ 2003;327:669–672, with permission. wide differences in normal semen parameters. Semen parameters may vary widely from one man to another and among men with proven fertility. In many circumstances, several specimens are necessary to verify an abnormality (30).


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Gynecology_Novak. Sperm Volume and pH The lower limit of normal semen volume is 1.5 mL or more and the pH should be 7.2 or higher. These parameters are affected mainly by the balance between the acidic secretions of the prostate gland and the alkaline ﬂuid from the seminal vesicles. Low volume along with pH less than 7 suggests obstruction of the ejaculatory ducts or absence of the vas deferens. Difficulties with collection, retrograde ejaculation, or androgen deficiency can contribute to low volume. High volumes greater than 5 mL suggest inﬂammation of the accessory glands (30). Sperm Concentration Sperm concentration or density is defined as the number of sperm per milliliter in the total ejaculate. The normal lower limit is 15 million/mL or more, recently revised from 20 million/mL or more (30,43). Only intact sperm are counted in determining sperm concentration. Fifteen percent to 20% of infertile men are azoospermic (no sperm) and 10% have a density of less than 1 million/mL (30,47).


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Gynecology_Novak. Sperm Motility and Viability Sperm motility is the percentage of progressively motile sperm in the ejaculate. The normal lower limit is 32% or more, recently revised from 50% or more (30,43). Viability should be at least 58%. Progressive motility refers to movement either linearly or in a large circle regardless of speed. Nonprogressive motility describes sperm that display only small movements or twitching or no movement at all (immotile). Assessments of speed of progression, either rapid or slow, have been removed from the revised guidelines because of difficulty in unbiased measurement of this parameter. A reduction in sperm motility is referred to as asthenozoospermia. Leukocytes can impair sperm motility through oxidative stress. When a large number of immotile sperm are present or when progressive motility is less than 40%,


Gynecology_Novak

Gynecology_Novak. Differential Diagnosis of Male Factor viability studies should be performed. Viable immotile sperm may have ﬂagellar defects, while the presence of nonviable immotile sperm (necrozoospermia) suggests epididymal pathology. Viable sperm have intact plasma membranes, which will not stain (dye exclusion) but will swell in hypoosmotic solutions (hypoosmotic swelling test) (30).


Gynecology_Novak

Gynecology_Novak. Sperm Morphology Morphology refers to anatomic malformations of the sperm. The lower limit for normal morphology is 4% or more using strict criteria, a change from previous guidelines using a more lenient assessment and a cutoff of 30% or more (30,43). Assessment of sperm morphology involves fixing and staining of a portion of the specimen. The strict Tygerberg criteria were introduced by Kruger et al. in 1986 to assess sperm morphology (30,48,49). Using this system, the entire spermatozoon—including the head, midpiece, and tail—is assessed, and even mild abnormalities in head forms are classified as abnormal. Most sperm from normal men exhibit minor abnormalities when subjected to Tygerberg standards. An abnormality of sperm morphology is known as teratozoospermia, and these sperm have poor fertilizing potential and may have abnormal DNA. A disadvantage to any morphology assessment is that reproducibility may be hampered by the subjective nature of the assessment (30).


Gynecology_Novak

Gynecology_Novak. Nonsperm Cells These include epithelial cells, round cells, and isolated sperm heads or tails. Round cells include immature germ cells and leukocytes. Immature germ cell elevation suggests testicular damage, while leukocytes (predominantly neutrophils) are associated with inﬂammation. Leukocytes can be distinguished by peroxidase positive staining, and normal leukocyte concentrations should be less than 1 million/mL. However, the prognostic significance of leukocytes in the semen is controversial (30,50). When bacterial colonization is found, the most common pathogens are Chlamydia trachomatis (41.4%), Ureaplasma urealyticum (15.5%), and Mycoplasma hominis (10.3%) (51).


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Gynecology_Novak. Antisperm Antibodies Antisperm antibodies, particularly those found on the surface of sperm, are associated with decreased pregnancy rates. Testing may be indicated with a history of ductal obstruction, prior genital infection, testicular trauma, and prior vasectomy reversal. It may be useful with oligozoospermia in the setting of normal hormonal levels, asthenospermia with normal sperm concentration, sperm agglutination, or unexplained infertility. Antisperm antibody testing is not needed if the sperm are to be used for intracytoplasmic sperm injection (ICSI) (44,47). Using the immunobead test, washed spermatozoa are exposed and assessed for binding to labeled beads. In the mixed agglutination reaction, human red blood cells sensitized with human immunoglobulin G (IgG) are mixed with the partner’s semen. Spermatozoa that are coated with antibodies form mixed agglutinates with the red blood cells (30).


Gynecology_Novak

Gynecology_Novak. Other Sperm Tests Although the standard semen analysis and associated tests provide a fairly reasonable picture of semen quality, they yield little information about sperm function. These specialized tests may be pursued to assess DNA integrity, fertilization potential (zona-free hamster oocyte test), and the effect of cervical mucus on sperm viability and function (postcoital test) (44,52). In general, these tests are not currently considered part of the standard assessment because their prognostic value and impact on management are limited by poor specificity, poor reproducibility, or controversies concerning the interpretation of the results (44,47,52).


Gynecology_Novak

Gynecology_Novak. If abnormalities in the semen are detected, further evaluation of the male partner by a urologist is indicated to diagnose the defect. Table 32.4 lists the differential diagnoses for male factor infertility (53). Several groups have attempted to assess the distribution of male infertility diagnoses; two such distributions are shown in Table 32.5 (54,55). The first is the result of a WHO study of 7,057 men with complete diagnoses based on the WHO standard investigation of the infertile couple (54). The figures include data from cases in which the male partner was normal and the presumed cause of the couple’s infertility was a female factor. The second distribution is the result of a study of 425 subfertile male patients (54). Although the two studies represent different populations (one is from a study of couples, the other from a urologic practice) and differ in their distribution of male infertility diagnoses, idiopathic male factor and varicocele predominate. Other anatomic and


Gynecology_Novak

Gynecology_Novak. is from a study of couples, the other from a urologic practice) and differ in their distribution of male infertility diagnoses, idiopathic male factor and varicocele predominate. Other anatomic and endocrine causes occur less frequently. Same sex female couples or single women without a male partner who desire pregnancy may be considered as part of this category.


Gynecology_Novak

Gynecology_Novak. Table 32.4 Etiologic Factors in Male Infertility From De Kretser DM. Male infertility. Lancet 1997;349:787–790, with permission. of autosomal dominant diseases such as achondroplasia and craniosynostotic conditions and somewhat higher rates of trisomy 21 (56). In mice, offspring of older fathers have decreased survival (57). Increased paternal age is associated with recurrent pregnancy loss (58). Treatment of Male Factor Not From Azoospermia


Gynecology_Novak

Gynecology_Novak. Medical treatment of reversible infectious or endocrine causes of male subfertility, such as sexually transmitted diseases and thyroid disorders, tends to be efficacious. Although injections of exogenous FSH have been reported to improve pregnancy rates, the benefit is less clear for clomiphene citrate, an estrogen antagonist at the hypothalamus and pituitary that promotes gonadotropin release. Exogenous testosterone is not recommended in the treatment of male subfertility because of negative feedback inhibition at the pituitary that results in decreased spermatogenesis, but the combination of testosterone and an antiestrogen may be of benefit. Antioxidant food supplements have been evaluated (59). Glutathione, carnitine, and vitamin E do not appear to affect semen parameters, but administration of zinc and folic acid were associated with improved sperm concentration and morphology (60). The diagnosis and treatment of azoospermia (no sperm on semen analysis) will be discussed


Gynecology_Novak

Gynecology_Novak. administration of zinc and folic acid were associated with improved sperm concentration and morphology (60). The diagnosis and treatment of azoospermia (no sperm on semen analysis) will be discussed separately from other forms of male factor infertility.


Gynecology_Novak

Gynecology_Novak. Table 32.5 Frequency of Some Etiologies in Male Factor Infertility No demonstrable cause 48.5 Varicocele 37.4 Idiopathic abnormal semen 26.4 Idiopathic 25.4 Varicocele 12.3 Testicular failure 9.4 Infectious factors 6.6 Obstruction 6.1 Immunologic factors 3.1 Cryptorchidism 6.1 Other acquired factors 2.6 Low semen volume 4.7 Congenital factors 2.1 Semen agglutination 3.1 Sexual factors 1.7 Semen viscosity 1.9 Endocrine disturbances 0.6 Other 5.9 TOTAL 103.9a 100 aMore than 100% because of multiple factors. From The ESHRE CAPRI Workshop Group. Male sterility and subfertility: guidelines for management. Hum Reprod 1994;9:1260–1264, and Burkman LJ, Cobbington CC, Franken DR, et al. The hemizona assay (HZA): development of a diagnostic test for the binding of human spermatozoa to the human hemizona pellucida to predict fertilization potential. Fertil Steril 1988;49:688–697, with permission.


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Gynecology_Novak. Varicocele Repair A varicocele is an abnormal dilation of the veins within the spermatic cord. Varicoceles are present in 15% of normal men and 40% of men seeking infertility treatment, but semen parameters are lower among infertile men with varicoceles (61,62). The pathophysiologic effects of a varicocele appear to be mediated by an associated rise in testicular temperature, reﬂux of toxic metabolites from the left adrenal or renal veins, or higher reactive oxygen species (61,63). Although treatment is associated with improved semen parameters in some studies, it is not clear whether varicocele repair definitely improves fertility (61,64,65). Treatment is typically considered if the varicocele is palpable and the semen analysis is abnormal, but is not indicated if IVF would be required to treat the female partner and the existing semen analysis would be acceptable for ICSI. Treatment methods include surgical repair and percutaneous embolization. Complications of treatment include


Gynecology_Novak

Gynecology_Novak. to treat the female partner and the existing semen analysis would be acceptable for ICSI. Treatment methods include surgical repair and percutaneous embolization. Complications of treatment include infection, varicocele persistence, recurrence, and hydrocele formation (61).


Gynecology_Novak

Gynecology_Novak. Artificial Insemination Artificial insemination has been used mainly to treat unexplained infertility (usually combined with superovulation) and male factor infertility (including same sex female couples). All artificial insemination procedures involve the placement of whole semen or processed sperm into the female reproductive tract, which permits sperm–ovum interaction in the absence of intercourse. The placement of whole semen into the vagina as a mode of fertility treatment is now rarely performed except in cases of severe coital dysfunction. Currently, all of the common forms of artificial insemination involve processed sperm obtained from the male partner or a donor. Many techniques for artificial insemination have been described, but only intracervical and intrauterine inseminations (IUI) have been routinely employed. The success rates with intracervical insemination are lower than those with IUI, particularly when using frozen sperm (66–68).


Gynecology_Novak

Gynecology_Novak. Insemination Processing During and after intercourse, seminal ﬂuid usually is prevented from reaching the intrauterine cavity and intra-abdominal space by the cervical barrier. The introduction of seminal ﬂuid past this barrier may be associated with pelvic infection and severe uterine cramping or anaphylactoid reactions, possibly mediated by seminal factors such as prostaglandins. Thus, protocols for processing whole semen include the washing of specimens to remove seminal factors and to isolate pure sperm. Additional processing may include centrifugation through density gradients, sperm migration protocols, and differential adherence procedures (66). Finally, phosphodiesterase inhibitors, such as pentoxiphylline, have been used during semen processing in an attempt to enhance sperm motility, fertilization capacity, and acrosome reactivity for IVF procedures (60,69). Azoospermia: Classification and Treatment


Gynecology_Novak

Gynecology_Novak. Intrauterine Insemination IUI is the best studied and most widely practiced of all the insemination techniques. It involves placement of about 0.3 to 0.5 mL of washed, processed, and concentrated sperm into the intrauterine cavity by transcervical catheterization (66). Patients should remain immobile for approximately 15 minutes following the procedure (70). Studies of the efficacy of IUI in the treatment of male factor infertility have been difficult to assess because of variations in inclusion criteria and the limitations of sperm function tests. Although it makes intuitive sense that IUI would result in higher pregnancy rates rather than timed intercourse in the case of male factor subfertility, there are conﬂicting reports of the benefits of IUI (66,71–74). Ideally, the total motile sperm count in the IUI specimen should be 5 million or 10 million or more (75–78). Pregnancy rates with semen meeting those thresholds have been reported to be 10.5% per cycle and 38% after 4 to 6


Gynecology_Novak

Gynecology_Novak. sperm count in the IUI specimen should be 5 million or 10 million or more (75–78). Pregnancy rates with semen meeting those thresholds have been reported to be 10.5% per cycle and 38% after 4 to 6 cycles (77,78). No benefit has been found with respect to double IUI versus single IUI during a single cycle (79).


Gynecology_Novak

Gynecology_Novak. Intracytoplasmic Sperm Injection In general, ICSI has allowed couples with male factor infertility to achieve assisted reproductive technology (ART) pregnancy outcomes that are comparable with those of couples with non–male factor infertility using conventional IVF treatment (80). ICSI has been used since 1992 to increase the fertilization rate of oocytes retrieved during ART by direct injection of a live sperm into the oocyte, thereby theoretically bypassing limitations imposed by sperm motility and defects in capacitation, the acrosome reaction, and/or sperm binding the zona pellucida (81). This microsurgical procedure involves stripping the aspirated cumulus complex of all surrounding granulosa cells, followed by insertion of a single viable sperm into the cytoplasm (ooplasm) of the mature metaphase II egg (9,82). ICSI should be offered if the semen analysis shows less than 2 million motile sperm, less than 5% motility, or if surgically recovered sperm are used. Its use for


Gynecology_Novak

Gynecology_Novak. the mature metaphase II egg (9,82). ICSI should be offered if the semen analysis shows less than 2 million motile sperm, less than 5% motility, or if surgically recovered sperm are used. Its use for abnormal morphology is more controversial (47,83). Immature or round spermatid nucleus injection (ROSNI) for ICSI is considered experimental at this time (84). Higher pregnancy rates have been noted with fresh compared to frozen specimens and with ejaculated compared to surgically retrieved sperm. Success rates are affected by the age of the female partner and oocyte quality (47). Non–male factor indications for ICSI include a history of fertilization failure with conventional IVF and the fertilization of oocytes before preimplantation genetic diagnosis (85). Other uses are described under “Unexplained Infertility.”


Gynecology_Novak

Gynecology_Novak. Risks of Intracytoplasmic Sperm Injection In skilled hands, oocyte damage with ICSI is reportedly 10% (81). However, oocyte degeneration can follow even an uncomplicated ICSI procedure, with rates as high as 30% to 50%. This is most likely a function of oocyte quality and/or patient factors rather than the ICSI process itself (82). Based on data from 5-year-old children, ICSI is associated with a higher congenital anomaly risk (4.2%) when compared with conventional IVF (typically 2% to 3%) (80). There may be an increased risk of imprinting disorders and hypospadias with ICSI (47). Reports indicate a slightly higher risk of sex chromosome abnormalities (0.8% to 1% ICSI vs. 0.2% IVF) and translocations (0.36% ICSI vs. 0.07% general population). It is unclear whether these relate to the ICSI procedure or inherent gamete defects; men with abnormal semen parameters have higher rates of sperm aneuploidy. Recent studies have not found an association with impaired intellectual or motor


Gynecology_Novak

Gynecology_Novak. ICSI procedure or inherent gamete defects; men with abnormal semen parameters have higher rates of sperm aneuploidy. Recent studies have not found an association with impaired intellectual or motor development among ICSI children. In the setting of specific genetic abnormalities such as Y chromosome microdeletions, abnormal karyotypes, cystic fibrosis mutations, or congenital absence of the vas deferens, genetic counseling should be offered to address the possible risk of infertility or other abnormality in the offspring (80).


Gynecology_Novak

Gynecology_Novak. Azoospermia describes the absence of spermatozoa in the ejaculate and is found in 1% of all men and up to 15% to 20% of infertile men. Causes are categorized into pretesticular (nonobstructive), testicular (nonobstructive), and posttesticular (includes obstructive and nonobstructive) etiologies, but in some cases the condition is idiopathic (47,86).


Gynecology_Novak

Gynecology_Novak. Pretesticular azoospermia is relatively rare and results from gonadotropin deficiency, which leads to loss of spermatogenesis. The physician should perform a full endocrine history that includes information on puberty and growth and check for low serum levels of LH, FSH, and testosterone (44,47,86). Prolactin levels and pituitary imaging are indicated in cases of hypogonadotropic hypogonadism (47). Hormonal treatment includes pulsatile gonadotropinreleasing hormone (GnRH), human chorionic gonadotropin, and exogenous gonadotropins (44,47,86). The best predictors of good response are postpubertal onset of gonadotropin deficiency and testicular volume greater than 8 mL (47).


Gynecology_Novak

Gynecology_Novak. Gonadal failure is the hallmark of testicular azoospermia. Causes of this condition may be genetic, acquired (e.g., radiation therapy, chemotherapy, testicular torsion, varicocele, or mumps orchitis), or developmental (e.g., testicular maldescent). Testicular atrophy is often present. Because of the low chance of obtaining sperm, testicular biopsy is generally not recommended with hypergonadotropic hypogonadism (elevated levels of LH and FSH with low serum levels of testosterone) and consideration should be given to using donor sperm. Diagnostic testicular biopsies may be indicated in the setting of normal hormonal testing. If sperm are present on diagnostic testing, consideration can be given to using surgically retrieved spermatozoa for ICSI (44,47,86). If no sperm are present, consideration can be given to correcting acquired conditions such as varicocele, which may restore sperm to the ejaculate to permit ICSI or spontaneous pregnancy (87,88). Chromosomal abnormalities by


Gynecology_Novak

Gynecology_Novak. consideration can be given to correcting acquired conditions such as varicocele, which may restore sperm to the ejaculate to permit ICSI or spontaneous pregnancy (87,88). Chromosomal abnormalities by peripheral karyotype testing are present in about 7% of infertile, 5% of oligospermic, and 10% to 15% in azoospermic men. Sex chromosome aneuploidies such as Klinefelter syndrome (47,XXY) encompass two-thirds of these infertility-associated chromosome abnormalities. Microdeletions in the Y chromosome have been identified in 10% to 20% of men with idiopathic azoospermia or severe oligospermia with concentration less than 5 million/mL (44,47,86) (Table 32.6). These microdeletions can be transmitted to the male offspring, who may then suffer from infertility. Therefore, screening for genetic causes is indicated in nonacquired cases of testicular azoospermia so that genetic counseling can be provided before treatment (80). The two most commonly implicated candidate gene families are the


Gynecology_Novak

Gynecology_Novak. causes is indicated in nonacquired cases of testicular azoospermia so that genetic counseling can be provided before treatment (80). The two most commonly implicated candidate gene families are the RNA-binding motif (RBM) and the “deleted in azoospermia” (DAZ) families, but microdeletions at various loci on the Y chromosome have been described (44,47,86,89–91). For example, microdeletions in Yq11.23 can occur in one or more of three regions: AZFa (proximal), AZFb (central), and AZFc (distal) (44,47,86).


Gynecology_Novak

Gynecology_Novak. Posttesticular or obstructive etiologies are associated with normal gonadotropin and testosterone levels and are present in up to 40% of azoospermic men (47,86). Ejaculatory dysfunction is associated with oligospermia or aspermia but rarely azoospermia (86). Obstructive causes include congenital absence or obstruction of the vas deferens or ejaculatory ducts, acquired obstruction of these ducts, or ductal dysfunction, including retrograde ejaculation (47,86). In the absence of congenital bilateral absence of the vas deferens (CBAVD) or hypogonadism, men with low volume ejaculate should have a postejaculatory urinalysis to check for retrograde ejaculation, which is associated with diabetes and surgery to the bladder or prostate (44,47). Sperm may be isolated from the neutralized urine of men with retrograde ejaculation and processed for insemination or for ART (30). Transrectal ultrasound may be of use to diagnose Table 32.6 Genetics and Male Infertility


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Gynecology_Novak. Table 32.6 Genetics and Male Infertility Congenital bilateral Cystic fibrosis F508, R117H 66 absence of vas (CFTR gene) deferens (CBAVD) Nonobstructive Karyotype 47, XXY 15–30 azoospermia AZFa, AZFba, 10–15 AZFc Severe (<5 M/mL) Karyotype 47, XXY 1–2 oligozoospermia Translocation 0.2–0.4 Y chromosome Partial AZFb, 7–10 microdeltions AZFc CFTR, cystic fibrosis transmembrane conductance regulator; AZF, azoospermia factor. aAZFb the most severe (DAZ gene—deleted in azoospermia) causes the most severe defects of spermatogenesis; AZFc causes the mildest defects of spermatogenesis. From Hirsh A. Male infertility. BMJ 2003;327:669–672, with permission.


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Gynecology_Novak. ejaculatory duct obstruction or unilateral vasal agenesis (to demonstrate contralateral atresia) but is generally not needed for CBAVD (86). Renal imaging is necessary when either unilateral or bilateral vasal absence is diagnosed as a result of the 10% to 25% incidence of renal agenesis. Most men with CBAVD will have seminal vesicle agenesis, so almost all will have low semen volume, low pH, and low fructose levels (86). Spermatogenesis can be expected to be normal in CBAVD, so generally diagnostic biopsy is not indicated (92). In some cases, testicular biopsy may be indicated to differentiate between testicular and posttesticular causes. At least two-thirds of men with CBAVD have mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR). However, because many CFTR mutations are undetectable, CBAVD patients should be assumed to have a mutation and thus testing of the female partner’s carrier status should be performed (86).


Gynecology_Novak

Gynecology_Novak. Vasectomy Reversal and Treatment of Obstructive Azoospermia Vasectomy can be reversed effectively using microsurgical vasovasostomy or vasoepididymostomy. These techniques can be used for epidymal obstructions (93). Patency and subsequent pregnancy rates approach 100% and 80%, respectively. Pregnancy typically occurs within 24 months of reversal (94). Rates of patency and pregnancy vary inversely with the length of time from vasectomy, particularly for reversal procedure performed after 15 years or more (93,94). Although 60% of reversal patients develop antisperm antibodies, these do not appear to affect fecundability. Following surgery, periodic semen analyses can identify reobstruction, which can range from 3% to 21% depending on which segments were anastamosed. For those patients with azoospermia 6 months after reversal, the procedure is considered a failure and testicular sperm aspiration with ICSI could be considered. However, repeat vasovasostomy is associated with patency rates


Gynecology_Novak

Gynecology_Novak. 6 months after reversal, the procedure is considered a failure and testicular sperm aspiration with ICSI could be considered. However, repeat vasovasostomy is associated with patency rates of 75% and pregnancy rates of 43% (94).


Gynecology_Novak

Gynecology_Novak. Surgical Sperm Recovery for Intracytoplasmic Sperm Injection Among the many surgical methods for sperm recovery, the most widely described are microsurgical epididymal sperm aspiration (MESA), percutaneous epididymal sperm aspiration (PESA), testicular sperm extraction (TESE), and percutaneous testicular sperm fine-needle aspiration (TESA, also called fine-needle aspiration, or FNA). Both MESA and TESE are open surgical procedures performed with an operating microscope and general or regional anesthesia, whereas the percutaneous procedures need only local anesthesia. The optimal choice for surgical sperm recovery method has not been determined and certainly varies based on patient history. Hematoma risk appears to be low regardless of method. Testicular atrophy is a rare complication of TESE and TESA even when biopsies are obtained from multiple testicular sites (92).


Gynecology_Novak

Gynecology_Novak. With obstructive azoospermia, pregnancy rates using sperm retrieval and ICSI are 24% and 64%, respectively, and outcomes using either frozen-thawed or fresh sperm are comparable. Because MESA allows for diagnosis and possible reconstruction of ductal pathology and because it usually yields very large numbers of sperm, sperm cryopreservation and avoidance of repeat surgery may be possible (92). If repeat sperm retrievals are needed, the minimum interval between procedures is 3 to 6 months to allow for adequate healing (93). For nonobstructive (testicular) azoospermia, epididymal aspiration is not an option. Although pregnancies have been reported following testicular sperm retrieval with nonobstructive azoospermia, the likelihood of retrieving sperm is low as are subsequent pregnancy rates (92,95). Patients with obstructive azoospermia must be counseled regarding the risk of transmitting genetic disorders to their offspring (47,86).


Gynecology_Novak

Gynecology_Novak. Donor Insemination For men with azoospermia, couples with significant male factor infertility who do not desire ART, or women without a male partner who are seeking pregnancy, therapeutic donor insemination offers an effective option (96). In several prospective randomized or crossover trials, IUI was shown to be superior to intracervical insemination for donor insemination (68). In patients younger than 30 years of age who have no other infertility factors, delivery rates approach 90% after 12 cycles of IUI treatment with frozen sperm, so patients who do not conceive within 6 to 12 months should be assessed for female factors and encouraged to terminate treatment or proceed with alternative forms of therapy. The concomitant use of clomiphene citrate or gonadotropin (hMG) for controlled ovarian hyperstimulation (COH) did not result in higher fecundity rates in these patients (97). Psychological counseling should be offered because of the potential repercussions of using donor gametes


Gynecology_Novak

Gynecology_Novak. hyperstimulation (COH) did not result in higher fecundity rates in these patients (97). Psychological counseling should be offered because of the potential repercussions of using donor gametes (96).


Gynecology_Novak

Gynecology_Novak. Donor Sperm Screening Although the use of fresh donor semen is associated with higher pregnancy rates than the use of frozen specimens, both the Centers for Disease Control and


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Gynecology_Novak. Prevention and the American Society for Reproductive Medicine recommend the use of frozen samples (96,98,99). This recommendation stems from the increasing incidence of human immunodeficiency virus (HIV) infection in the general population and the lag time between HIV infection and seroconversion. Currently, semen donors are screened for HIV infection, hepatitis B, hepatitis C, syphilis, gonorrhea, chlamydia, and cytomegalovirus infections, all of which may be transmitted through semen. All cryopreserved samples are quarantined for 6 months, and the donor is retested for HIV before clinical use of the specimen. Donors are likewise questioned about any family history of genetically transmitted disorders, including both Mendelian (e.g., hemophilia, Tay-Sachs disease, thalassemia, cystic fibrosis, congenital adrenal hyperplasia, Huntington disease) and polygenic or multifactorial conditions (e.g., mental retardation, diabetes, heart malformation, spina bifida). Those with a positive


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Gynecology_Novak. fibrosis, congenital adrenal hyperplasia, Huntington disease) and polygenic or multifactorial conditions (e.g., mental retardation, diabetes, heart malformation, spina bifida). Those with a positive family history of these conditions are eliminated as donor candidates (96).


Gynecology_Novak

Gynecology_Novak. Figure 32.4 Live births per embryo transfer comparing use of a patient’s own versus donor oocytes. (Adapted from CDC Reproductive Health. 2009 Assisted Reproductive Technology Success Rates. National Summary and Fertility Clinic Reports. http://www.cdc .gov/nccdphp/drh/art.htm.) Successful live birth is dependent on the age of the eggs used, not on the age of the mother. Women in their 40s can achieve the same pregnancy success rates as 25year-olds if they use donor eggs that are provided by younger women.


Gynecology_Novak

Gynecology_Novak. Reproductive aging is associated with abnormalities in the oocyte meiotic spindles that lead to chromosome alignment errors and increase rates of conceptus aneuploidies, particularly trisomies. This serves to increase the risk for spontaneous pregnancy loss and thereby decrease live birth rates in older women (100,105). A large study based on the Danish national registry estimated the rates of clinically recognized spontaneous pregnancy loss for various age groups to be 13.3% (12 to 19 years), 11.1% (20 to 24 years), 11.9% (25 to 29 years), 15.0% (30 to 34 years), 24.6% (35 to 39 years), 51.0% (40 to 44 years), and 93.4% (older than 45 years) (106). In addition, using sensitive hCG assays in women during their reproductive years, 22% of all pregnancies were found to be lost before they could be clinically diagnosed (107).


Gynecology_Novak

Gynecology_Novak. Ovarian reserve refers to the size of the nongrowing, or resting, primordial follicle population in the ovaries. This, in turn, presumably determines the number of growing follicles and the “quality” or reproductive potential of their oocytes (105). Tests of ovarian reserve are often used, but the predictive values of these tests for fertility potential are limited, particularly when normal testing is found in older women and abnormal testing is documented in younger women. The tests appear to be better suited for determining how the ovaries will respond to pharmacologic doses of exogenous gonadotropins in terms of follicle count, the number of oocytes produced, serum estradiol levels during stimulation, the duration of stimulation, and the quantity of exogenous gonadotropins required in a given cycle (108). However, unlike age, the results of ovarian reserve testing are poorly predictive of pregnancy outcomes (109–111). These tests appear to be more indicative of oocyte quantity


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Gynecology_Novak. in a given cycle (108). However, unlike age, the results of ovarian reserve testing are poorly predictive of pregnancy outcomes (109–111). These tests appear to be more indicative of oocyte quantity rather than quality (110).


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Gynecology_Novak. Serum Day 3 Follicule Stimulating Hormone As women age, FSH physiologically rises in the early follicular phase (cycle day 3), with levels of 5.74 IU/L at age 35 to 39 and 14.34 IU/L at age 45 to 59. Higher levels are seen after unilateral oophorectomy. In women in their 40s, levels greater than 20 IU/L are predictive of menopause. Because the incidence of abnormal values is lower in younger women, testing is typically performed for women aged 35 or older (108). In subfertile women with an FSH 8 IU/L or more, spontaneous pregnancy rates decrease by 7% per unit of FSH increase, with a 40% reduction at 15 IU/L and 58% at 20 IU/L (112). FSH levels vary widely by assay, laboratory, and population (109). Because of the poor sensitivity of high basal FSH values in determining fecundability, they should not be used as the sole basis for excluding women from consideration for ART (113). Likewise, the poor specificity of low basal FSH values in determining fecundability makes them unreliable


Gynecology_Novak

Gynecology_Novak. should not be used as the sole basis for excluding women from consideration for ART (113). Likewise, the poor specificity of low basal FSH values in determining fecundability makes them unreliable when used to reassure patients, particularly those of increased reproductive age (109).


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Gynecology_Novak. Basal Estradiol Level Basal day 3 FSH is often combined with estradiol (E2) testing. Estradiol levels on day 3 of the menstrual cycle reﬂect follicular growth rather than the number of antral follicles (114). Elevations in FSH and decreases in inhibin B (see below) that accompany aging results in advanced follicular growth at the end of the preceding luteal phase. In response, early follicular E2 levels are typically higher in older women and in women with advanced reproductive aging (104).


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Gynecology_Novak. Clomiphene Citrate Challenge Test Clomiphene citrate is thought to have antiestrogenic effects on the hypothalamic–pituitary axis, resulting in a decrease in E2-mediated suppression of FSH production by the pituitary. The clomiphene citrate challenge test (CCCT) involves the measurement of serum FSH and estradiol on day 3 of the menstrual cycle, and again on day 10 after administration of clomiphene citrate (100 mg orally each day) from days 5 to 9. The CCCT has been reported to be more sensitive than basal FSH alone in identifying poor response to exogenous gonadotropins, but others report that the predictive values of the tests do not differ substantially (109,110).


Gynecology_Novak

Gynecology_Novak. Serum Inhibin B Serum inhibin B is secreted by ovarian granulosa cells starting at the preantral follicle stage and therefore reﬂects the size of the growing follicular cohort (111). Reduced inhibin B levels are seen with aging even in normal fertile women (114). Inhibin B alone has poor predictive value for ovarian response but improves the predictive value when added to the CCCT (109,110). Unlike basal testing, levels of inhibin B measured on the 5th day of ovarian stimulation were predictive of live birth following IVF/ICSI (115). Serum Antim¨ullerian Hormone Antim¨ullerian hormone (AMH) is produced by the granulosa cells of preantral and small antral follicles (111,114). The serum level of AMH in women with normal cycles declines with age and becomes undetectable after menopause (114,116).


Gynecology_Novak

Gynecology_Novak. AMH appears to be a good predictor of both excessive (>3.5 ng/mL) and poor (<1 ng/mL) IVF stimulation response and is strongly correlated to the antral follicle count (111,116,117). Unlike other serum markers, AMH can be measured at any time in the menstrual cycle (116). Antral Follicle Count Using transvaginal ultrasound in the early follicular phase, all ovarian follicles 2 to 10 mm are counted and the total for both ovaries is called the basal antral follicle count (AFC). The AFC correlates well with chronologic age in normal fertile women and appears to reﬂect what remains of the primordial follicular pool (104). Decreases in AFC with age are gradual rather than sudden (118). A total AFC less than 4 is predictive of poor response and higher cancellation rates with IVF (119,120).


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Gynecology_Novak. Treatment of Diminished Ovarian Reserve Treatments of diminished ovarian reserve include autologous IVF, use of donor oocytes or embryos, and adoption. Pretreatment of women with diminished ovarian reserve for 4 to 5 months with dehydroepiandrosterone (DHEA; 25 mg three times daily) has been described to improve oocyte yield and pregnancy rates with IVF (121–123).


Gynecology_Novak

Gynecology_Novak. Ovulatory Factor Ovulatory factor accounts for 30% to 40% of all cases of female infertility. Initial diagnoses among women with ovulatory factor infertility may include anovulation (complete absence of ovulation) or oligo-ovulation (infrequent ovulation). Menstrual history may be suggestive if oligomenorrhea, amenorrhea, polymenorrhea, or dysfunctional uterine bleeding is present (124). Menstrual dysfunction is present in 18% to 20% of the general population (125). Figure 32.5 shows the ﬂuctuations of E2, progesterone, FSH, and LH in a normal, 28-day ovulatory cycle. The normal length of the menstrual cycle in reproductive-age women varies from 21 to 35 days, with a mean of 27 to 29 days (126). Most of the variability in cycle length occurs during the follicular phase (127), but the luteal phase, often considered to be fixed at 14 days, can range from 7 to 19 days (128). Even women with regular monthly menses may have anovulation, although the presence of moliminal symptoms such as


Gynecology_Novak

Gynecology_Novak. phase, often considered to be fixed at 14 days, can range from 7 to 19 days (128). Even women with regular monthly menses may have anovulation, although the presence of moliminal symptoms such as premenstrual breast swelling, bloating, and mood changes are much more suggestive of ovulatory cycles (125).


Gynecology_Novak

Gynecology_Novak. Methods to Document Ovulation The “Fertile Window” The fertile window is the 6 day interval ending on the day of ovulation, but not after ovulation. Sperm can survive for up to 6 days in well-estrogenized cervical mucus, but the egg may be fertilizable for less than a day. Daily intercourse during this window may increase the probability of conception (32,127). The average woman is fertile between days 10 and 17 of the menstrual cycle, but many women can conceive outside of this range (128). Therefore, if timed intercourse is too cumbersome, intercourse two to three times weekly throughout the menstrual cycle will likely result in at least some of those occasions falling within the fertile window (129). Duration of abstinence prior to the fertile window has not been established, although one author suggests 5 days (127).


Gynecology_Novak

Gynecology_Novak. Basal Body Temperature This inexpensive method involves daily recording of oral or rectal temperature using a basal body temperature (BBT) thermometer before the patient arises, eats, or drinks. The secretion of progesterone following ovulation causes a temperature increase of about 0.5 to 1◦F over the baseline temperature of 97◦F to 98.8◦F that is typically recorded during the follicular phase of the menstrual cycle. Ovulation is assumed after 3 consecutive days of raised temperatures. Charting of daily BBTs produces a characteristic biphasic pattern in women with ovulatory cycles (130). Limitations to BBT include its inability to prospectively predict ovulation and its frequent false-negative results (131). Smoking and irregular sleep patterns can interfere with accurate BBT testing (130).


Gynecology_Novak

Gynecology_Novak. Cervical Mucus During the fertile window, cervical secretions at the vaginal introitus are slippery and clear, while secretions at other times of the menstrual cycle are dry and sticky (32,130). The volume of cervical mucus peaks 2 to 3 days prior to ovulation, thus identifying higher day-specific probabilities of conception (32).


Gynecology_Novak

Gynecology_Novak. Luteinizing Hormone Monitoring At a mean time of 2 hours following the peak of the serum LH surge, urinary LH can be detected. Commercially available kits for documenting the LH surge are generally accurate, quick, convenient, and relatively inexpensive enzyme-linked immunosorbent assays (ELISA) that use 35 to 50 mIU/mL as their threshold for detection (132,133). Once the LH surge is detected, ovulation may occur within the next 48 hours (32,132,133). The positive-predictive and negative-predictive values for these kits have been described to be 92% and 95%, respectively (132,134). Because the duration of the surge may be less than 12 hours, twice daily testing may increase detection rates (133). However, the 2 days of highest probability of conception are the day of and the day prior to the LH surge, so this may actually lead to abstaining from intercourse during a potentially fertile time (127). False-positive rates occur in 7% of cycles, which may reﬂect urinary clearance of


Gynecology_Novak

Gynecology_Novak. to the LH surge, so this may actually lead to abstaining from intercourse during a potentially fertile time (127). False-positive rates occur in 7% of cycles, which may reﬂect urinary clearance of unsustained premature LH surges (32,131,135). The tests cannot be used in patients with irregular cycles (127).


Gynecology_Novak

Gynecology_Novak. Midluteal Serum Progesterone When used to document ovulation, serum progesterone measurement should coincide with peak progesterone secretion in the midluteal phase (typically on days 21 to 23 of an ideal 28-day cycle or 7 days following the LH surge). The lower limit of progesterone levels in the luteal phase varies among laboratories, but a level above 3 ng/mL (10 nmol/L) typically confirms ovulation. However, interpretation of isolated luteal-phase measurements of serum progesterone is complicated by the frequent pulses that characterize the secretion of this hormone. Although ovulatory levels are often considerably higher than 3 ng/mL, low midluteal serum levels of progesterone are not necessarily diagnostic of anovulation (124).


Gynecology_Novak

Gynecology_Novak. Ultrasound Monitoring Ovulation is characterized both by a decrease in the size of a monitored ovarian follicle and by the appearance of ﬂuid in the cul-de-sac using transvaginal ultrasound (124). Follicles reach a preovulatory diameter of 17 to 19 mm in spontaneous cycles or 19 to 25 mm for clomiphene-induced cycles (136,137). A combination of LH testing and ultrasound can be used, with LH kit testing starting when the ultrasound-measured follicle size reaches 14 mm (131). Ten percent of the cycles of normally fertile women may have a luteinized unruptured follicle, whereby progesterone is released and the luteal phase progresses normally without visible signs of follicle rupture when daily ultrasounds are performed from cycle days 10 to 20. This incidence is increased to 25% in women with unexplained infertility (138). Because of the inconvenience and expense of serial measurements, ultrasound monitoring should be reserved for patients who fail less expensive methods for detecting


Gynecology_Novak

Gynecology_Novak. unexplained infertility (138). Because of the inconvenience and expense of serial measurements, ultrasound monitoring should be reserved for patients who fail less expensive methods for detecting ovulation or for certain types of ovulation induction (124).


Gynecology_Novak

Gynecology_Novak. Follow-Up Tests In women with absent or infrequent ovulation, serum FSH, prolactin, and thyroid-stimulating hormone (TSH) testing should be performed (124). The most common cause of oligo-ovulation and anovulation—both in the general population and among women presenting with infertility—is polycystic ovarian syndrome (PCOS) (139). The diagnosis of PCOS is determined by exclusion of other medical conditions such as pregnancy, hypothalamic–pituitary disorders, or other causes of hyperandrogenism (e.g., androgen-secreting tumors or nonclassical congenital adrenal hyperplasia) and the presence of two of the following conditions (140): Oligo-ovulation or anovulation (manifested as oligomenorrhea or amenorrhea) Hyperandrogenemia (elevated levels of circulating androgens) or hyperandrogenism (clinical manifestations of androgen excess)


Gynecology_Novak

Gynecology_Novak. Hyperandrogenemia (elevated levels of circulating androgens) or hyperandrogenism (clinical manifestations of androgen excess) Documentation of elevated serum LH:FSH ratios and hyperinsulinemia are not required for either diagnosis or treatment of PCOS (139,140). Patients with PCOS should be counseled and screened regarding potential metabolic disease and obstetric complications prior to fertility treatment (141). Ovulation Induction in Women with Polycystic Ovarian Syndrome


Gynecology_Novak

Gynecology_Novak. Ovulation Induction in Women with Polycystic Ovarian Syndrome Despite the use of similar medications, the indications and goals of ovulation induction should be distinguished from those of superovulation. The goal of ovulation induction refers to the therapeutic restoration of the release of one egg per cycle in a woman who either has not been ovulating regularly or has not been ovulating at all. In contrast, the explicit goal of superovulation is to cause more than one egg to be ovulated, thereby increasing the probability of conception in women with unexplained infertility (136).


Gynecology_Novak

Gynecology_Novak. Weight Loss Obesity in PCOS patients is associated with poor infertility treatment outcomes (139,142–144), although the impact on pregnancy loss rates is less clear (141,142,145). Given that even a 5% weight loss may improve pregnancy rates, weight loss should be encouraged in all overweight and obese infertility patients (139). Generally, lifestyle modification is the first-line therapy, followed by pharmacologic treatment and weight-loss surgery (139). Lifestyle recommendations include a decrease in daily caloric consumption by 500 kcal and regular physical exercise, although the optimal regimen for the latter is unknown (139,146). Weight loss interventions should be undertaken prior to attempting conception in patients with excess body weight (139).


Gynecology_Novak

Gynecology_Novak. Clomiphene Citrate (Clomid, Serophene) Pharmacology Clomiphene citrate is a weak synthetic estrogen that mimics the activity of an estrogen antagonist when given at typical pharmacologic doses for the induction of ovulation. It is cleared through the liver and excreted into the stool, with 85% clearance in 6 days. A functional hypothalamic–pituitary–ovarian axis is usually required for appropriate clomiphene citrate action. More specifically, clomiphene citrate is thought to bind and block estrogen receptors in the hypothalamus for prolonged periods, thereby decreasing the normal ovarian–hypothalamic estrogen feedback loop. This blockade increases GnRH pulsatility, leading to increased pituitary secretion of gonadotropins, which promote ovarian follicular development (136).


Gynecology_Novak

Gynecology_Novak. Clomiphene Citrate Outcomes Clomiphene is considered a first-line treatment for anovulatory infertility (147). Over the course of 6 months, clomiphene is associated with 49% ovulation, 23.9% pregnancy, and 22.5% live birth rates in women with anovulatory infertility (142). Clomiphene effectiveness is decreased by obesity, increased age, and hyperandrogenic states (142,148,149). Side effects of clomiphene citrate include vasomotor ﬂushes, mood swings, breast tenderness, pelvic discomfort, and nausea. In a minority of individuals, the antiestrogenic effects of clomiphene citrate at the level of the endometrium or the cervix may have adverse effects on fertility. In the presence of visual abnormalities, clomiphene citrate should be discontinued promptly. Multiple gestation rates with clomiphene citrate are approximately 8%, most of which are twins (136). Treatment should be limited to 6 ovulatory cycles or 12 total cycles (141,150,151).


Gynecology_Novak

Gynecology_Novak. Clomiphene Citrate Dosing The drug is supplied in 50 mg tablets; the usual starting dose is 50 mg per day, but patients who are very sensitive may respond to 12.5 to 25 mg per day. Therapy is typically begun within the first 5 days after the onset of a spontaneous or progesterone-induced menses and is continued for 5 days (i.e., treatment on days 2 to 6, 3 to 7, or 5 to 9 of the menstrual cycle) (136). It has been reported to be effective when started the day following progesterone withdrawal therapy, without waiting for menses (152). If ovulation does not occur at the initial dosage of clomiphene citrate, the dosage is increased in each subsequent cycle by 50 mg per day. Seventy-four percent of women will ovulate with 100 mg per day, the maximum dose approved by the U.S. Food and Drug Administration (153). However, some patients need higher doses, which have been safely given up to 250 mg per day (136). A novel stair-step method has been proposed, which increases the dose within a


Gynecology_Novak

Gynecology_Novak. Administration (153). However, some patients need higher doses, which have been safely given up to 250 mg per day (136). A novel stair-step method has been proposed, which increases the dose within a single cycle without intervening menses if there was no follicular response documented by ultrasound 4 to 5 days after the last pill (154). However, this particular protocol raises concern for unknown endometrial and embryonic effects (155).


Gynecology_Novak

Gynecology_Novak. Ovulation Monitoring during Clomiphene Citrate Therapy If preovulation monitoring is not performed, patients should be instructed to have intercourse every 2 to 3 days following the last day of therapy and check a serum progesterone weekly for 5 weeks before inducing a withdrawal bleed or increasing the clomiphene citrate dose (142). Although no clear advantage has been demonstrated for any ovulation monitoring technique, regular contact should be maintained with patients to review response to therapy. The urinary LH surge may be detected 5 to 12 days after treatment is completed. When clomiphene is given cycle days 5 to 9, the surge typically occurs on cycle day 16 or 17 and can be confirmed by midluteal serum progesterone testing 7 days later. With ultrasound monitoring, treatment should be withheld if large cysts are seen on baseline testing. Following clomiphene, follicles typically reach a preovulatory diameter of 19 to 25 mm by ultrasound, but may be as large as 30 mm (136,137).


Gynecology_Novak

Gynecology_Novak. be withheld if large cysts are seen on baseline testing. Following clomiphene, follicles typically reach a preovulatory diameter of 19 to 25 mm by ultrasound, but may be as large as 30 mm (136,137). A combination of LH testing and ultrasound can be used, with LH kits starting when the largest ultrasound-measured follicle reaches 14 mm in diameter (131).


Gynecology_Novak

Gynecology_Novak. Human Chorionic Gonadotropin If a dominant follicle develops, but there is no spontaneous LH surge, human chorionic gonadotropin (hCG) can be used to induce final follicular maturation, with ovulation occurring approximately 40 hours following administration (136,156). Although administration of hCG at midcycle does not appear to improve conception chances in most infertility patients using clomiphene citrate, it may be useful for patients with known ovulatory dysfunction (157–159). The medication may be derived from urine (5,000 to 10,000 IU intramuscularly) or manufactured with recombinant technology (250 μg subcutaneously, equivalent to 5,000 to 6,000 IU urinary) (156).


Gynecology_Novak

Gynecology_Novak. Timing of Intrauterine Insemination When IUI is added to the therapeutic protocol, insemination typically is performed 24 hours following the LH surge (157). However, given data that ovulation can occur much later than this, it is not surprising that no differences in pregnancy rates were found when IUI was performed between 24 and 60 hours following the LH surge (160). Although timing of IUI is typically performed 36 hours following hCG administration to coincide with follicle rupture when hCG is added to trigger ovulation, no significant differences in pregnancy or live birth rates are seen whether IUI is performed at 24 or 36 hours following the hCG trigger (161).


Gynecology_Novak

Gynecology_Novak. Insulin Sensitizers Insulin resistance is thought to play a central role in the pathogenesis of PCOS (Table 32.7). Metformin is an oral biguanide that is approved for the treatment of non– insulin-dependent diabetes and has been used in PCOS to increase the frequency of spontaneous ovulation. Metformin acts by several mechanisms, including inhibition of gluconeogenesis in the liver and increasing the uptake of glucose in the periphery (162). Although the literature is conﬂicting, larger studies have suggested that the live birth rate with metformin alone (7.2%) is lower than that achieved with clomiphene, and the combination does not confer additional benefit over clomiphene alone (142,163). Obese patients are less likely to respond to metformin (164). It remains unclear whether metformin decreases miscarriage rates in PCOS, Table 32.7 Clinical Findings that Suggest Insulin Resistance and Hyperinsulinemia Physical findings associated with insulin resistance


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Gynecology_Novak. Table 32.7 Clinical Findings that Suggest Insulin Resistance and Hyperinsulinemia Physical findings associated with insulin resistance Waist-to-hip ratio >0.85 From Barbieri RL. Induction of ovulation in infertile women with hyperandrogenism and insulin resistance. Am J Obstet Gynecol 2000;183:1412–1418, with permission.


Gynecology_Novak

Gynecology_Novak. although it appears to be safe when used during pregnancy (142,162). Risks of metformin include gastrointestinal upset and rare lactic acidosis, so it should be avoided in settings of hepatic and renal dysfunction and prior to surgery or use of contrast radiologic dye. Reported effective doses include 500 mg three times daily, 850 mg twice daily, or 1,000 mg twice daily (142,162). The medication is best tolerated when started at the lowest dose and increased gradually. Extended release formulations are associated with less gastrointestinal upset (142). Because regular ovulation may be delayed for 3 to 6 months or may not occur with metformin alone, patients may need medications to induce withdrawal bleeding to mitigate the risk of continued anovulation and endometrial hyperplasia (141). Thiazolidinediones, which include rosiglitazone and pioglitazone, have been used for ovulation induction in PCOS patients (165–168). They have less associated gastrointestinal upset than metformin. All


Gynecology_Novak

Gynecology_Novak. which include rosiglitazone and pioglitazone, have been used for ovulation induction in PCOS patients (165–168). They have less associated gastrointestinal upset than metformin. All carry the risk of liver toxicity and, in the case of rosiglitazone, cardiovascular harm, and they are typically avoided during pregnancy (141).


Gynecology_Novak

Gynecology_Novak. Dexamethasone Adjunctive oral dexamethasone may improve ovulation rates in patients resistant to clomiphene alone (147). These improvements have been reported even in the absence of adrenal hyperandrogenemia, so the mechanism of action remains unclear (169,170). Dose regimens have included 0.5 mg for 5 days starting on the first day of clomiphene, 0.5 mg for 6 weeks prior to starting clomiphene, and 2 mg for 10 days starting on the first day of clomiphene (169–172). Oral Contraceptive Pretreatment Administration of oral contraceptives for 2 months prior to beginning a cycle of clomiphene may improve ovulation and pregnancy rates in clomipheneresistant patients, perhaps by improving a preexisting hyperandrogenic environment (147,173).


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Gynecology_Novak. Tamoxifen Tamoxifen is an oral antiestrogen similar in structure to clomiphene that is commonly used as an adjuvant therapy for breast cancer but has been used off-label to induce ovulation (174). Ovulation and pregnancy rates are similar with tamoxifen and clomiphene (147,174). Doses start at 20 mg per day for 5 days (similar in timing to clomiphene), and can be increased to 40 or 60 mg per day in subsequent cycles. The mechanism of action for tamoxifen in inducing ovulation appears to be similar to that of clomiphene, although tamoxifen exerts less negative endometrial effects (175).


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Gynecology_Novak. Aromatase Inhibitors These drugs include letrozole and anastrazole. Through their inhibition of aromatase-mediated conversion of androgens to estrogens and subsequent decreases in circulating estradiol, aromatase inhibitors have been approved for treatment of breast cancer. The off-label use of letrozole for ovulation induction in clomiphene-resistant patients was first reported in 2001 (176). Typical doses are 2.5 to 5 mg of letrozole or 1 mg of anastrazole daily for 5 days. Timing of administration is similar to that of clomiphene, although longer durations of 10 days have been reported (177,178). Letrozole appears to have less negative effects on endometrial development when compared to clomiphene (176). Although concerns have been raised regarding possible associations between fetal congenital anomalies and the use of aromatase inhibitors, no such increase was observed when letrozole was compared to clomiphene (179). Patients should be counseled regarding the absence of


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Gynecology_Novak. fetal congenital anomalies and the use of aromatase inhibitors, no such increase was observed when letrozole was compared to clomiphene (179). Patients should be counseled regarding the absence of prospective, sufficiently powered studies to assess safety of off-label use of aromatase inhibitors for ovulation induction (141).


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Gynecology_Novak. Gonadotropin Therapy Anovulatory PCOS patients who fail to ovulate or conceive with oral agents should be considered for ovulation induction with exogenous gonadotropin injections. Evening medication administration allows for morning monitoring and midday decision making. Monitoring involves serum estradiol levels and transvaginal ultrasound measurements of follicle development. Typical protocols monitor at baseline, 4 to 5 days after treatment initiation, then every 1 to 3 days until follicular maturation (expected follicle growth is 1 to 2 mm daily after achieving 10 mm diameter) (180). Given the goal of promoting growth of a single mature follicle, low initial gonadotropin doses of 37.5 to 75 IU per day are generally recommended, with increases in doses by 50% of the previous dose after 7 days if no follicle greater than 10 mm is observed (141,180). Typical treatment duration is 7 to 12 days, but some patients require longer medications regimens for adequate stimulation. The


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Gynecology_Novak. after 7 days if no follicle greater than 10 mm is observed (141,180). Typical treatment duration is 7 to 12 days, but some patients require longer medications regimens for adequate stimulation. The maximum required gonadotropin dose seldom exceeds 225 units per day. Ovulation triggering with hCG is recommended for gonadotropin cycles and is used when one or two follicles are 16 to 18 mm in diameter and the E2 level per dominant follicle is 150 to 300 pg/mL. Ovulation can be expected 24 to 48 hours after the hCG trigger. GnRH agonists such as leuprolide (500 μg subcutaneously) can be used to trigger ovulation, but they require progesterone supplementation following administration. Intercourse should be recommended within 24 to 48 hours of ovulation triggering or IUI 24 to 36 hours after triggering (180). Testing for pregnancy should be performed 15 to 16 days after ovulation triggering and the cycle reviewed if pregnancy testing is negative. Gonadotropin dosage in future cycles should


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Gynecology_Novak. (180). Testing for pregnancy should be performed 15 to 16 days after ovulation triggering and the cycle reviewed if pregnancy testing is negative. Gonadotropin dosage in future cycles should be altered if the prior response was inadequate or excessive.


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Gynecology_Novak. Gonadotropin Preparations Several gonadotropin preparations are available. Human menopausal gonadotropin (HMG) is derived from human urine and includes approximately equivalent FSH and LH (derived from hCG) activity of 75 IU each. Current formulations of HMG and FSH can be administered either subcutaneously or intramuscularly. FSH-only preparations may be derived either from urine or via recombinant methods and are packaged either as lyophilized powder or premixed-liquid cartridges/pens. With the exception of highly purified urinary FSH, which has an FSH activity of 82.5 IU per ampule, all other products contain 75 IU of gonadotropin when supplied in ampules. All preparations of FSH are highly purified, with minimal to no batch-to-batch variation and a high level of safety regardless of the derived source. Despite being differentially marketed as follitropin-α and -β, these recombinant FSH preparations still contain combinations of 1-α and 1-β glycoprotein chain. Rather, they differ


Gynecology_Novak

Gynecology_Novak. the derived source. Despite being differentially marketed as follitropin-α and -β, these recombinant FSH preparations still contain combinations of 1-α and 1-β glycoprotein chain. Rather, they differ in their posttranslational modifications and processes for purification. Recombinant LH is available in syringes delivering 75 IU (156). For PCOS patients, FSH alone (either recombinant or urinary) appears to be sufficient in the gonadotropin preparation, although LH is not harmful (180) (Table 32.8). Contraindications to gonadotropin therapy are listed in Table 32.9.


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Gynecology_Novak. Gonadotropin Outcomes Cumulative live birth rates are similar when gonadotropins are compared to clomiphene for ovulation induction when the goal is monofollicular ovulation and a maximum of six ovulatory cycles is similarly recommended (141). When compared to other anovulatory patients, PCOS patients using gonadotropins are at higher risk for multiple gestations (36%), ovarian hyperstimulation syndrome (4.6%), and cycle cancellation (10%) because of their high numbers of baseline antral follicles (141,180, 181). Cancellation should be strongly considered in patients who reach E2 levels 1,000 to 2,500 pg/mL, have three or more follicles 16 mm or larger, or two or more follicles 16 mm or larger plus two or more follicles 14 mm or larger (141). Sequential use of gonadotropins and either clomiphene or aromatase inhibitors has been associated with lower gonadotropin requirements and lower cancellation rates and treatment duration without compromising pregnancy rates. The addition of


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Gynecology_Novak. clomiphene or aromatase inhibitors has been associated with lower gonadotropin requirements and lower cancellation rates and treatment duration without compromising pregnancy rates. The addition of aromatase inhibitors is associated with a lower number of dominant follicles and lower maximum E2 levels (182–184).


Gynecology_Novak

Gynecology_Novak. Table 32.8 Different Types of Available Gonadotropin Preparations FSH, follicle-stimulating hormone; LH, luteinizing hormone; hMG, human menopausal gonatropin; IM, intramuscularly; SC, subcutaneously; N/A, not applicable. Table 32.9 Contraindications to Gonadotropins for the Treatment of Infertility in Women 1. Primary ovarian failure with elevated follicle-stimulating hormone levels 2. 3. An organic intracranial lesion such as a pituitary tumor 4. 5. 6. Prior hypersensitivity to the particular gonadotropin 7. Sex hormone–dependent tumors of the reproductive tract and accessory organs 8. From Physicians desk reference. Micromedex (R) Healthcare Series Vol. 107. Thompson PRD and Micromedex Inc., 1974–2004, with permission.


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Gynecology_Novak. Surgical Treatment For clomiphene-resistant patients, surgical ovarian drilling has been performed as an alternative to the outdated ovarian wedge resection in an effort to decrease ovarian androgen-producing tissue and to promote ovulation without the risk of multiple pregnancy seen with gonadotropin administration (141,185). Drilling 3 to 15 puncture sites per ovary is typically performed via laparoscopy using electrocautery and diathermy or laser, although transvaginal ultrasound-guided and vaginal hydro-laparoscopy procedures have been reported (186–195). Successful drilling has been performed with the harmonic scalpel (190). Within 12 months after ovarian drilling, cumulative ovulation, clinical pregnancy, and live birth rates are 52%, 26% to 48%, and 13% to 32%, respectively. These outcomes are similar to those using gonadotropins, but ovarian drilling carries a lower multiple gestation rate. Outcomes are not significantly different when diathermy or laser are used for drilling,


Gynecology_Novak

Gynecology_Novak. are similar to those using gonadotropins, but ovarian drilling carries a lower multiple gestation rate. Outcomes are not significantly different when diathermy or laser are used for drilling, but they are compromised with patient age greater than 35 years or basal FSH greater than 10 mIU/mL (185,187). The risks of ovarian drilling include surgical complications, adhesions, recurrence of anovulation, and a theoretical risk of ovarian failure (185,196).


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Gynecology_Novak. Hyperprolactinemia Hyperprolactinemia can be associated with oligomenorrhea or amenorrhea and should be evaluated with pituitary magnetic resonance imaging (MRI) to exclude macroadenoma or other intracranial pathology (197). Dopamine agonists are first-line agents in otherwise asymptomatic oligoovulatiory or anovulatory patients to restore ovulation (197). Bromocriptine normalizes prolactin levels and induces ovulation in 80% to 90% of patients. It is taken two to three times daily, and most patients will respond to a total dose less than 7.5 mg daily. Side effects can be bothersome and include nausea, vomiting, postural hypotension, and headache. Cabergoline has similarly high efficacy and the advantage of a 0.25 mg twice-weekly dosing schedule and fewer side effects (198).


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Gynecology_Novak. Hypogonadotropic Hypogonadism Anovulation in the presence of low serum LH, FSH, and estradiol levels defines hypogonadotropic hypogonadism and reﬂects dysfunction within the hypothalamic–pituitary axis. Causes of hypogonadotropic hypogonadism, including craniopharyngiomas, pituitary adenomas, arteriovenous malformations, or other central space-occupying lesions, should be excluded using MRI. Stress, extreme weight loss, anorexia, excessive exercise, and low body mass index are all associated with functional hypothalamic suppression, so good nutrition and optimal body weight should be encouraged to restore ovulation (197,199). Leptin is a hormone produced by peripheral adipocytes that reﬂects energy stores and is deficient in women with diet or exericise-induced amenorrhea (200). Exogenous leptin has been reported to restore ovulation in these women (200,201). Other conditions of hypothalamic dysfunction, such as congenital hypothalamic failure (Kallmann syndrome), can be treated using


Gynecology_Novak

Gynecology_Novak. leptin has been reported to restore ovulation in these women (200,201). Other conditions of hypothalamic dysfunction, such as congenital hypothalamic failure (Kallmann syndrome), can be treated using pulsatile GnRH therapy or gonadotropins. In these patients, both FSH and LH should be administered (197,202). Pulsatile GnRH agonist therapy (25 ng/kg every 60 to 90 minutes) simulates normal physiology and offers some advantages over gonadotropin injections, including fewer multiple gestations and less ovarian hyperstimulation syndrome (OHSS) while maintaining excellent pregnancy rates (202).


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Gynecology_Novak. Hypothyroidism The prevalence of hypothyroidism among mid-reproductive aged women is 2% to 4% and is mostly a result of autoimmune factors. Menstrual abnormalities, including those from anovulation, are present in 23% to 68% of overtly hypothyroid women and can be corrected with levothyroxine replacement. Subclinical hypothyroidism and the presence of antithyroid antibodies (even if euthyroid) are associated with increased rates of infertility and spontaneous pregnancy loss, although there exists a lack of consensus as to appropriate upper normal limits of TSH and selection bias limits interpretation. In any case, because even very mild or subclinical hypothyroidism can have adverse effects on fetal brain development and subsequent intelligence quotient, it is prudent to screen and treat women with thyroid hormone abnormalities before commencing infertility treatment (203).


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Gynecology_Novak. Tubal Factor Tubal factor accounts for 25% to 35% of infertility. Noninfectious causes for tubal factor include tubal endometriosis, salpingitis isthmica nodosa, tubal polyps, tubal spasm, and intratubal mucous debris (10). The incidence of tubal infertility has been reported to be 8%, 19.5%, and 40% after one, two, and three episodes of PID, respectively (204). Live birth rates are negatively affected by the severity of a single episode of PID (205). C. trachomatis and Neisseria gonorrhoeae are common pathogens associated with PID and infertility. M. hominis and U. urealyticum have been implicated in PID, but their contribution to infertility is less clear (17). Many patients with documented tubal damage have no history of PID and are presumed to have had subclinical chlamydial infections (206,207).


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Gynecology_Novak. Hysterosalpingography Hysterosalpingography (HSG) is performed after menses but prior to ovulation between cycle days 7 and 12 to avoid potential pregnancy and take advantage of the thinner proliferative phase endometrium. The patient is typically premedicated 30 to 60 minutes prior to the procedure with ibuprofen or related medication (208). Lidocaine injected intracervically may provide further pain relief (209). With the patient in the dorsal lithotomy position, either a metal cannula or a balloon catheter is inserted through the cervix and past the internal cervical os. Contrast dye is then injected under ﬂuoroscopy to visualize the uterine cavity, fallopian tube architecture, and tubal patency (208,210). Certain disease processes, such as salpingitis isthmica nodosa, have a characteristic appearance on HSG, with typical cornual or isthmic honeycombing resulting from contrast-filled diverticular projections (211). Compared to laparoscopy, HSG has a sensitivity and specificity of


Gynecology_Novak

Gynecology_Novak. appearance on HSG, with typical cornual or isthmic honeycombing resulting from contrast-filled diverticular projections (211). Compared to laparoscopy, HSG has a sensitivity and specificity of 86.5% and 79.8% for bilateral tubal patency and 90% and 97% for bilateral tubal occlusion, respectively. The specificity of HSG remains high but the sensitivity drops for unilateral tubal patency (212).


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Gynecology_Novak. Hysterosalpingography Risks Although use of oil-based contrast has been associated with higher pregnancy rates following HSG when compared to water-based contrast (213,214), water-based contrast is generally preferred to avoid oil embolism or granuloma formation. Furthermore, patients should be screened for and pretreated with glucocorticoids if iodine allergy is found (210). The risk of PID after HSG is 0.3% to 3.1% overall but is greater than 10% in the setting of hydrosalpinges (215,216). Therefore, HSG should be avoided in the setting of known hydrosalpinges and/or current or suspected PID (208,216). The role of routine antibiotic prophylaxis for HSG is controversial, but in high-risk patients doxycycline could be considered (217). Recommended dosing is 100 mg twice daily, beginning the day before HSG and continuing for 3 to 5 days. If prophylaxis is not used and hydrosalpinges are noted on examination, postprocedure doxycycline treatment is recommended. Other rare complications


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Gynecology_Novak. the day before HSG and continuing for 3 to 5 days. If prophylaxis is not used and hydrosalpinges are noted on examination, postprocedure doxycycline treatment is recommended. Other rare complications of HSG include vascular intravasation, cervical laceration, uterine perforation, hemorrhage, vasovagal reactions, severe pain, and allergic response to the contrast dye (208).


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Gynecology_Novak. Chlamydia Serology Chlamydia antibody testing appears to have comparable sensitivity and specificity to HSG but does not localize pathology and the utility of testing is controversial (211). It has been proposed that positive serologies in the setting of normal HSG should still prompt laparoscopy to rule out peritubal adhesions (207). Laparoscopy Laparoscopy is considered the gold standard for diagnosing tubal and peritoneal disease. It allows visualization of all pelvic organs and permits detection and potential concurrent treatment of intramural and subserosal uterine fibroids, peritubal and periovarian adhesions, and endometriosis. Abnormal findings on HSG can be validated by direct visualization on laparoscopy using chromopertubation, which involves the transcervical installation of a dye such as indigo carmine to directly visualize tubal patency and fimbrial architecture (212). However, even laparoscopy has been reported to have a false-positive rate of 11%


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Gynecology_Novak. Treatment of Tubal Factor Infertility for proximal tubal occlusion when resected tubal segments are examined pathologically (218).


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Gynecology_Novak. Other Diagnostic Modalities Falloposcopy is used in conjunction with hysteroscopy and allows direct fiberoptic visualization of tubal ostia and intratubal architecture for identification of tubal ostial spasm, abnormal tubal mucosal patterns, and even intraluminal debris causing tubal obstruction (218,219). At present, instrumentation availability and technical complications, including tubal perforation, limit its routine use (219). Alternatively, sonohysterography offers a much less invasive method of diagnosing fallopian tubal obstruction. The use of contrast media during sonohysterography is preferred to improve accuracy in documenting fallopian tubal patency, but these contrast agents are not available in the United States. As a substitute, the use of agitated saline (air-saline) during sonohysteroscopy provides good negative predictive value when compared to HSG or laparoscopy (220).


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Gynecology_Novak. As success rates for ART continue to improve, the indications for surgical approaches in the treatment of tubal infertility have become increasingly limited (221). Still, surgery can be effective in several situations and may be the optimal approach in some patients.


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Gynecology_Novak. Proximal Tubal Occlusion Proximal tubal catheterization and cannulation performed either via HSG or hysteroscopy can restore tubal patency in up to 85% of obstructions, although the reocclusion rate approaches 30%. The best candidates for proximal tubal catheterization or cannulation have muscle spasm, stromal edema, amorphous debris, mucosal agglutination, or viscous secretions, while nonresponders include those with luminal fibrosis, failed tubal reanastamosis, fibroids, congenital atresia, or tuberculosis. Occlusion from salpingitis isthmica nodosa, endometriosis, synechiae, salpingitis, and cornual polyps only occasionally will respond to catheterization or cannulation (10). Catheterization involves passage of a soft catheter into the tubal ostia, while cannulation passes a guidewire thru the ostia and injects contrast media or colored dye. Tubal perforation, typically minor, occurs in 1.9% to 11% of cases (10,211,218). Catheterization under ﬂuoroscopy during HSG is referred to as


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Gynecology_Novak. the ostia and injects contrast media or colored dye. Tubal perforation, typically minor, occurs in 1.9% to 11% of cases (10,211,218). Catheterization under ﬂuoroscopy during HSG is referred to as selective salpingography (222). Visualization of patency with the hysteroscopic approach can be accomplished using laparoscopy or ultrasound (10,218). Ongoing pregnancy rates following proximal tubal catheterization or cannulation are 12% to 44% regardless of hysteroscopic or HSG approach. If occlusion persists or recurs, IVF is usually recommended. Microsurgical tubocornual anastomosis is an option with small studies reporting pregnancy rates of up to 68% (10). This procedure typically is performed via laparotomy and involves excision of the tubal isthmus, followed by reimplantation of the residual tube into a new opening made through the uterine cornua (211).


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Gynecology_Novak. Distal Tubal Occlusion (Excluding Sterilization or Hydrosalpinx) Distal tubal disease and occlusion are causal in 85% of all tubal infertility and can be secondary to a variety of inﬂammatory conditions including infection, endometriosis, or prior abdominal or pelvic surgery (211,223). Patients younger than 35 years of age with mild distal tubal disease, normal tubal mucosa, and absent or minimal pelvic adhesions are the best candidates for corrective microsurgery (223). In vitro fertilization should be considered for older patients or those with diminished ovarian reserve, combined proximal and distal tubal disease, severe pelvic adhesions, tubal damage that is not amenable to reconstruction, or additional infertility factors (223,224). Fimbrioplasty involves lysis of fimbrial adhesions or dilation of fimbrial phimosis, whereas salpingostomy (also known as salpingoneostomy) involves the creation of a new tubal opening in an occluded fallopian tube (223). In well-selected patients,


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Gynecology_Novak. or dilation of fimbrial phimosis, whereas salpingostomy (also known as salpingoneostomy) involves the creation of a new tubal opening in an occluded fallopian tube (223). In well-selected patients, pregnancy rates are reported to be 32% to 42.2%, 54.6% to 60%, 30% to 34.6%, and 55.9% for adhesiolysis, fimbrioplasty, salpingostomy, and nonsterilization-related anastamosis, respectively (211,223). As a group, these procedures are associated with a 7.9% rate of subsequent ectopic pregnancy (223).


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Gynecology_Novak. Sterilization Reversal Twenty percent of women express regret following sterilization, and 1% to 5% of those will request reversal, often after a change in marital status. The technique for sterilization reversal involves microsurgical dissection of the occluded ends of the fallopian tube followed by a layered reapposition of the proximal and distal tubal segments. Surgical approaches include minilaparotomy, laparoscopy, and robotic-assisted laparoscopy (224,225). Pregnancy rates following microsurgical tubal reanastamosis for sterilization reversal are 55% to 81%, with most pregnancies occurring within 18 months of surgery (224). Ectopic pregnancy rates following the procedure are generally less than 10% but may approach 18% (223,226). The main predictors of success are age younger than 35 years, isthmic-isthmic or ampulo-ampullar anastamosis, final anastamosed tubal length greater than 4 cm, and less-destructive sterilization methods such as use of rings or clips (224,226). Unlike


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Gynecology_Novak. 35 years, isthmic-isthmic or ampulo-ampullar anastamosis, final anastamosed tubal length greater than 4 cm, and less-destructive sterilization methods such as use of rings or clips (224,226). Unlike vasectomy reversal, the length of time between fallopian tubal sterilization and reversal does not seem to affect outcome. IVF should be considered in lieu of sterilization reversal for older patients or those with diminished ovarian reserve, severe pelvic adhesions, additional infertility factors, or prior unsuccessful reanastamosis (223,224).


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Gynecology_Novak. Hydrosalpinx Distal occlusion may lead to ﬂuid buildup in the fallopian tube, causing a hydrosalpinx. Hydrosalpinx ﬂuid impedes embryo development and implantation (211). A meta-analysis of 14 studies and 1,004 patients with hydrosalpinges concluded that IVF pregnancy rates were significantly lower in the presence of hydrosalpinges (227). Salpingectomy for hydrosalpinx prior to IVF significantly improves both pregnancy and live birth rates when compared to IVF performed with the fallopian tubes in situ, although laparoscopic tubal occlusion appears to be a reasonable alternative (228–230). There are significantly less outcome data on the use of transvaginal needle drainage and salpingostomy for treatment of hydrosalpinges prior to IVF (211).


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Gynecology_Novak. Uterine Factors Pathologies within the uterine cavity are the cause of infertility in as many as 15% of couples seeking treatment and are diagnosed in greater than 50% of infertile patients (231). Therefore, the evaluation of the couple with infertility should consistently include an assessment of the endometrial cavity. Uterine cavity abnormalities include endometrial polyps, endometrial hyperplasia, submucous myomas, intrauterine synechiae, and congenital uterine anomalies (232).


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Gynecology_Novak. Hysteroscopy Hysteroscopy is considered the gold standard for uterine cavity evaluation because it allows for direct visualization. The procedure involves insertion of an endoscope through the cervical canal into the uterine cavity and instillation of distension media to allow for visualization (231–233). Diagnostic hysteroscopy may be performed in the office using a small-diameter hysteroscope and saline distension, often without need for anesthesia (232). To optimize visualization of the endometrial cavity and avoid performing the procedure during early pregnancy, hysteroscopy is typically scheduled during the early-to midfollicular phase of the cycle. Disadvantages to the procedure include poor visualization when uterine bleeding is present and the inability to evaluate structures outside the uterine cavity, including those in the myometrium and adnexa. Office hysteroscopy is reported to have a 72% sensitivity for cavity abnormalities when compared to operative hysteroscopy using


Gynecology_Novak

Gynecology_Novak. the uterine cavity, including those in the myometrium and adnexa. Office hysteroscopy is reported to have a 72% sensitivity for cavity abnormalities when compared to operative hysteroscopy using general anesthesia (231).


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Gynecology_Novak. Hysterosalpingogram Insofar as it allows assessment of both tubal and intrauterine pathology, HSG is a reasonable initial imaging technique to use in the basic infertility evaluation. Hysterosalpingogram shows the general configuration of the uterine cavity and indicates endometrial lesions as filling defects or irregularities of the intrauterine wall. Excessive contrast may lead to false-negative findings, which may account for the 50% sensitivity of HSG compared to hysteroscopy for endometrial polyps. Inability to discriminate air bubbles, mucous, and debris from true intracavitary pathology may account for HSG’s high false-positive rate when compared with hysteroscopy (232,233). Other drawbacks include patient discomfort, use of iodinated contrast, and radiation exposure (232).