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Infertility and Age

Fecundability

This information is extremely important when analyzing data concerning the results of various treatment methods applied to a group of infertile couples. Group includes those with hypofertility due to presumed causes (e.g., mild endometriosis) as well as those with idiopathic (unexplained) infertility. to determine that any method of treatment of infer-tility is superior to no treatment, the treatment results on the incidence of pregnancy over time need to be statistically analyzed.

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Term is generally used to indicate that a couple has a reduced capacity to conceive as compared with the mean capacity of the general population.

Both older and more recent studies indicate that the percentage of infertile couples increases with increasing age of the female partner. Because a woman's reproductive life span is limited to a certain number of years, if couples intend to have children, they should be counseled to maximize the length of time during which they attempt to conceive. Because the percentage of couples with decreased rates of fecundity increases with age of the female partner, couples should be informed that the probability of conception is substantially reduced by delaying childbearing until later in life. This reduction is caused by two factors: (1) the incidence of infertility increases with increasing age of the woman and (2) the total length of time during which conception is possible is less in older women. Because the occurrence of monthly ovulation decreases greatly after age 45, as a woman becomes older, a corresponding decrease occurs in the total duration of time during which she may conceive.

therapy should be offered to the couple only if it is found that such therapy hastens the time in which conception will take place as compared with untreated controls or couples with a similar duration of infertility and a normal diagnostic infertility evaluation. Couples with unexplained infertility, treatment with controlled ovarian hyperstimulation and intrauterine insemination has been shown to increase fecundability compared with no treatment, as has in vitro fertilization. Diagnostic Evaluation Diagnostic evaluation of infertility should be thorough and completed as rapidly as possible During the initial interview the couple should be informed about normal human fecundability and how these probabilities decrease with increasing age of the female partner over age 30 and duration of infertility for more than 3 years. Each couple should be instructed about the optimal time in the cycle for conception to occur and should be encouraged to have intercourse on the day before ovulation. Husband has oligospermia, daily intercourse for 3 consecutive days at midcycle should be encouraged. When ovulation is more precisely determined as with luteinizing hormone (LH) monitoring (see the following discussion), intercourse should occur for 2 consecutive days around the LH surge. Because the egg disintegrates less than a day after it reaches the ampulla of the oviduct, it is best that sperm be present in this area when the egg arrives so that fertilization can occur Normal sperm retains its fertilizing ability for up to 72 hours, it is preferable to have sperm in the oviduct prior to the arrival of the oocyte. Peak levels of LH occur 1 day before ovulation, measurement of LH by urinary LH immunoassays is the best way to determine the optimal time to have intercourse or insemination Tests that measure LH in a random daily urine specimen are usually more convenient for planning natural or artificial insemination than the tests that detect LH in the first morning urine specimen. Ovulation most commonly occurs on the day following the detection of LH in a random specimen (12 to 24 hours later), and it occurs on the day when LH is detected in the first morning specimen, which contains urine formed during the prior night. All couples should have a complete history taken, including a sexual history, and a physical examination. After this initial evaluation, tests should be undertaken to determine if the woman is ovulating and has patent oviducts and if a semen sample of the male partner is normal.
D i f O l o u m a n a t n o v c t u t i o o n a

Preliminary information that the woman is ovulatory is pro-vided by a history of regular menstrual cycles. If the woman is having regular menstrual cycles, a serum progesterone level should be measured in the midluteal phase to provide indirect evidence of ovulation as well as normal luteal function. Although in the normal luteal phase serum progesterone levels vary in a pulsatile manner, a serum progesterone level above 10 ng/mL is indicative of adequate luteal function. Measurement of daily BBT also provides indirect evidence that ovulation has taken place. The BBT graph also provides information concerning the approximate day of ovulation and duration of the luteal phase. The BBT should be taken shortly after awakening only after at least 6 hours of sleep and prior to ambulating, with sublingual placement of a special thermometer with gradients between 96 and 100 F. Women with oligomenorrhea (menses at intervals of 35 days or longer) or amenorrhea who wish to conceive should be treated with agents that induce ovulation regardless of whether they have occasional ovulatory cycles. Therefore, for such women direct or indirect measurement of progesterone is unnecessary until after therapy is initiated.
I I S A l e m n e n a y s i .

Male partner should be advised to abstain from ejaculation for 2 to 3 days before collection of the semen sample, because frequent ejaculation lowers seminal volume and occasionally the sperm count in some individuals. It is best to collect the specimen in a clean (not necessarily sterile), widemouthed jar after masturbation. It is important that the entire specimen be collected, because the initial fraction contains the greatest density of sperm. Ideally, collection should take place in the location where the analysis will be performed. The degree of sperm motility should be determined as soon as possible after liquefaction, which usually occurs 15 to 20 minutes after ejaculation. Sperm motility begins to decline 2 hours after ejaculation, and it is best to examine the specimen within this time period. Semen should not be exposed to marked changes in temperature, and if collected at home during cold weather, the specimen should be kept warm during transport to the laboratory. The last parameter should be evaluated in terms of percentage of total motile sperm as well as quality of motility (rapidity of movement and amount of progressive motility). Sperm morphology is an extremely important parameter, which is correlated to fertilizing ability. Using strict criteria (Kruger) only approximately 15% or more of the sperm in an ejaculate may be considered normal.


T b l

It should be remembered that the sperm analysis is a subjective test and that there is a fair degree of variability from test to test in the same man. Also the semen profile reflects sperm production, which occurred 3 months earlier, which is important to note if there were illness at that time.
4 1 4
S A l i N l R f V e m n e n a y s s

Varicocele and other anatomic disorders Maturation arrest Hypospermatogenesis Exogenous factors Abnormal volume No ejaculate Ductal obstruction Retrograde ejaculation Ejaculatory failure Hypogonadism Low volume Obstruction of ejaculatory ducts Absence of seminal vesicles and vas deferens Partial retrograde ejaculation Infection High volume Abnormal motility Unknown factors Immunologic factors Infection Varicocele

Volume pH Viscosity

1.55.0 mL >7.2 <3 (Scale 04)

Sperm concentration >20 million mL Total sperm number >40 million ejaculate Percent motility >50%

Forward progression >2 (scale 04) Normal morphology >50% normal >30% normal >14% normal Round cells <5 million mL

Sperm agglutination < (Scale 03)

T b l

Abnormal count Azoospermia Klinefelter's syndrome or other genetic disorders Sertoli-cell-only syndrome Seminiferous tubule or Leydig cell failure Hypogonadotrophic hypogonadism Ductal obstruction, including Young's syndrome Varicocele Exogenous factors Oligozoospermia Genetic disorder Endocrinopathies, including androgen receptor defects Extraneous cells Abnormal viscosity

Defects in sperm structure Metabolic or anatomic abnormalities of sperm Poor liquefaction of semen Etiology unknown

Abnormal morphology Varicocele Stress Infection Exogenous factors Unknown factors Infection or inflammation

Shedding of immature sperm

e s t s I I I E l i d L b v a a t n a n a r a o t r . o o u y T

Aspects of the woman's medical history that should be highlighted include the following: *any pregnancy complications if previously pregnant *previous pelvic surgery of any type *significant dysmenorrheal *dyspareunia or sexual dysfunction *abnormal cervical cytology or procedures to treat cervical *abnormalities *use of medication, drugs, and tobacco. Family history should be explored for genetically related illnesses, birth defects, and most importantly the history of age of menopause in female family members. Finally any symptoms suggestive of endocrine disorders should be solicited (weight changes, skin changes, etc.). Physical exam should focus on extremes of body mass, skin changes, thyroid size, breast secretion, abnormal pain on abdominal or pelvic exam, and assessment of the vagina and cervix. Healthy asymptomatic woman, only a complete blood count (CBC), blood type, RH, and rubella status are needed together with a Pap smear obtained within 12 months of the previous test. Cystic fibrosis screening is currently recommended in all women. Infections disease screening (for chlamydia and gonorrhea) is carried out routinely in most practices at the time of the Pap smear. Further infectious disease screening (syphilis, HIV, hepatitis, etc.) is warranted only on a selective basis and is required for all couples undergoing insemination or IVF. Women older than 35, serum follicle-stimulating hormone (FSH) and estradiol (E2) should be obtained on cycle day 2 or 3. , suggesting decreased ovarian reserve, which is the pool of viable oocytes remaining in the ovary;
V l

These tests are usually normal, and even if abnormalities are present in women with regular ovulatory cycles, these hormones may not be associated with infertility Treatment with thyroid replacement and bromocriptine has not been shown to increase the chance of conception in women with ovulatory cycles compared with no therapy. If an abnormality is found in one of the first two noninvasive diagnostic procedures (documentation of ovulation and semen analysis), it should be treated before proceeding with the more costly and invasive procedures, unless there is a history or findings suggestive of tubal disease If these initial diagnostic tests are normal, the more uncomfortable and costly hysterosalpingography (HSG) should be performed in the follicular phase of the next cycle.
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although FSH levels tend to fluctuate from cycle to cycle, once FSH has been elevated in a given cycle, the overall prognosis is reduced. E2 levels if elevated on days 2 and 3 (>70 pg/mL) do not allow for a valid interpretation of FSH values and may independently suggest a decreased prognosis regarding ovarian reserve. Routine measurement of thyroid-stimulating hormone (TSH) and prolactin in women with regular ovulatory cycles at the time of the initial visit may not be cost-effective

Schedule the HSG during the week following the end of menses to avoid irradiating a possible pregnancy Still routinely advise using prophylactic antibiotics at the time of HSG Prescribe doxycycline (100 mg twice a day for 4 days starting 1 day before the procedure), but this recommendation is not universally followed. If a hydrosalpinx is seen at HSG, doxycycline should be continued for 1 week. A water-soluble contrast medium enables better visualization of the tubal mucosal folds and vaginal markings than does an oil-based medium. It is important to be able to evaluate the appearance of the intra-tubal architecture to determine the extent of damage to the oviduct Diagnostic HSG will not only determine whether the tubes are patent but also, if disease is present, will help to determine the magnitude of the disease process as well as provide information about the lining of the oviduct and uterine cavity that cannot be obtained by laparoscopic visualization. The procedure can also determine whether salpingitis isthmica nodosa is present in the inter-stitial portion of the oviduct. Diagnostic laparoscopy may be considered to detect the presence of peritubal adhesions. The finding of a normal endometrial cavity at the time of HSG obviates the need for hysteroscopy At the time of laparoscopy following a normal HSG, neither a dilation and curettage nor hysteroscopy should be routinely performed. However, hysteroscopic tubal cannulation and other adjunctive procedures may be indicated on an individual basis.
d i i l t n a T e s t o s f T S H d P l i i O l e a u s e m n e o a n o n n v r t r c t u o t r y o

p a

If women with anovulation have hypothyroidism or hyperprolactinemia, treatment with thyroid replacement or dopamine agonists

Diagnosis of luteal deficiency can be determined by finding serum progesterone levels consistently below 10 ng/mL a week before menses or finding consistent histologic evidence of a delay in development of the normal secretory endometrial pattern, indicating an inadequate effect of progesterone production on the endometrium Because the onset of the next menses is the least accurate parameter for determining if luteal deficiency exists, the diagnosis of this entity occurs more frequently when this technique is used to establish the diagnosis than when pelvic sonography is used
l i C f I f i l m m u n o g a u s e s o e r t i t o n y c

VI.

I f

Autoimmunity to sperm in both semen and serum has been found in some infertile men, particularly those who have had testicular infection, injury, or a surgical procedure such as vasectomy reversal. Men with these antibodies have been treated with corticosteroid therapy and sperm-washing techniques.
e c t i o n

pregnancy outcome of women with long-standing infertility who conceive after treatment Ovulation-inducing drugs and reconstructive tubal surgery have independently been shown to be associated with an increased incidence of ectopic pregnancy compared with the normal population Use of ovulation-inducing drugs alone, as well as when combined with IVF and GIFT, has been shown to increase the incidence of multiple gestations. if conception occurs after treatment with either ovulation induction or tubal reconstructive surgery, monitoring of the early gestation with serial HCG measurements and ultrasonography assists in determining whether or not the pregnancy is intrauterine and how many gestational sacs are present. Management of Causes of Infertility
A l n o v u t i o n a

e a

A.

infection of the female reproductive tract could interfere with normal sperm transport urrent name now used for those organisms is Two other microorganisms of the genus that are found in the female genital tract are and
l

C l i h i m p n e o

Therapeutic agents currently available to induce ovulation are clomiphene citrate, urinary gonadotropins (HMG and other more FSHenriched preparations), recombinant FSH recombinant LH and colleagues and coworkers and associates gonadotropin-releasing hormone (GnRH). if anovulation is due to hyperprolactinemia, dopamine agonists are an effective means of inducing ovulation
l

Prognosis All infertile couples should be informed of the prognosis for pregnancy associated with treatment of their particular cause of infertility The highest probability of conception with treatment other than ARTs occurs among couples in whom anovulation is the only abnormality, with a substantially lower probability of pregnancy with tubal disease or sperm abnormalities Controlled ovarian hyperstimulation (COH) with either clomiphene citrate or human menopausal gonadotropin (HMG) followed by intrauterine insemination (IUI) also increase pregnancy rates compared with no treatment during short time intervals Woman older than 40 or in couples with marked abnormalities in the semen analysis, IVF with or without intracytoplasmic sperm injection (ICSI) should be recommended. Outcome of Pregnancy

Clomiphene citrate is the usual first-line pharmacologic agent for treating women with oligomenorrhea as well as those with amenorrhea who have sufficient ovarian E2 production. This synthetic, weak estrogen acts by competing with endogenous circulating estrogens for estrogen-binding sites on the hypothalamus, thereby blocking the negative feedback of endogenous estrogen. GnRH is then released in a normal manner, stimulating FSH and LH, which in turn cause oocyte maturation with increased E2 production. The drug is usually given daily for 5 days beginning 3 to 5 days after the onset of spontaneous menses or withdrawal bleeding induced with progesterone in oil or an oral progestin. During the days the drug is ingested, serum levels of LH and FSH rise, accompanied by a steady increase in serum E2 After ingestion of clomiphene citrate is discontinued, E2 levels continue to increase, and the negative feedback on the hypothalamic-pituitary axis causes a decrease in FSH and LH, similar to the change seen in the late follicular phase of a normal ovulatory cycle. About 5 to 9 days (mean 7 days) after the last clomiphene citrate tablet has been ingested, the exponentially rising level of E2 from the dominant

follicle has a positive feedback effect on the pituitary or hypothalamus, producing a surge in LH and FSH, which usually results in ovulation and luteinization of the follicle. ***Various treatment regimens have been advocated for the use of clomiphene citrate. Most start with an initial dosage of 50 mg per day for 5 days beginning on the fifth day of spontaneous or induced menses. If presumptive evidence of ovulation occurs with this dosage, the same dosage of clomiphene citrate is ingested in subsequent cycles until conception occurs. If ovulation fails to occur with the initial dosage, a sequential, graduated, increasing dosage regimen has proven to be effective with a minimum of side effects. With this regimen if ovulation does not occur with the 50-mg dose, the dosage of drug is increased in the next treatment cycle to 100 mg/day for 5 days. If ovulation does not occur with 100 mg/day in subsequent cycles, the dosage is sequentially increased to 150 mg, 200 mg, and finally 250 mg for 5 days. If ovulation is induced with any of these dosages, the woman is maintained on her individualized ovulatory dosage until conception occurs. If ovulation does not occur with 250 mg, in the next cycle 250 mg is given daily for 5 days, and 1 week after the last tablet has been ingested, 5000 IU of HCG is given to increase the chances of inducing ovulation by simulating the LH surge. In the 10 years' experience with this treatment regimen reported by Gysler and associates about half the women who ovulated and half those who conceived did so following treatment with the 50 mg/day regimen, and an additional one fifth did so with the 100 mg/day dosage. However, about one fourth of all women who ovulated or conceived did so following treatment with a higher dosage regimen, indicating the value of the individualized sequential treatment regimen. However, from a practical standpoint it is unusual to use doses higher than 150 mg, particularly when adjuncts are available such as metformin or switching to letrozole. ***If cysts are present, they will regress spontaneously without therapy, but if additional clomiphene citrate is given and further gonadotropin release is induced, stimulation and further enlargement of the cyst may occur. Clinically palpable ovarian cysts occur in about 5% of women treated with clomiphene citrate but in less than 1% of treatment cycles. The cysts usually range in size from 5 to 10 cm and do not require surgical excision as they nearly always regress spontaneously. Cysts can occur in any treatment cycle with any dosage, and the incidence is not increased with the higher dosages of drug. ***Some data suggest that in women with elevated levels of dehydroeipandrosterone sulfate (DHEA-S), use of low doses of dexamethasone may enhance the ovulationinducing effect of clomiphene.
M f i d O h I l i S i e t o r m n a n t e r u s n n e s t i z e r n s

considered an adjunctive treatment for ovulation induction and for most women with polycystic ovary disease (PCOS) is being considered now as first-line therapy. biguanine, which is used for diabetes. Its principal role is in reducing hepatic glucose production and thus commensurately decreasing hyperinsulinemia. However, it also has a direct effect on the ovary. metformin has been shown to induce ovulation in women with PCOS as well as in other anovulatory women who do not meet the criteria for the diagnosis. Its mechanism of action in inducing ovulation is both through reducing insulin resistance (and thereby affecting gonadotropins and androgens (see Chapter 4 , Reproductive Endocrinology) as well as directly stimulating the ovary. Typical dose of metformin is 1500 mg/day. It is preferable to use longacting tablets (XR or ES) in 500- and 750-mg tablets and to ingest them all at the same time at dinner. It should be begun, however, only at 500 mg and titrated up over several weeks. This is because of gastrointestinal effects (nausea, vomiting) Lactic acidosis is a very rare complication that occurs pri-marily in older individuals. However, checking chemistry blood levels after 3 months of metformin is good practice, and women also should be reminded not to drink alcohol heavily, although the occasional drink is acceptable
l i d P i l a t z o n e a n g i a t z o n

In insulin-resistant patients with PCOS, the diabetic drugs (thiadolazimediones) may induce ovulation by improving the insulinhormone axis as well as through direct effort on the ovary. These drugs have also been added to clomiphene therapy. However, this therapy should be reserved for short-term use under special circumstances. There is only a small risk of hepatic enzyme changes (unlike troglitazone, which is no longer available), but there is also a tendency for weight gain with long-term treatment.
o l

W
i h e g t a

Aromatase inhibitors are efficacious as primary agents for ovulation induction. There is the most experience with letrozole. The mechanism of action is that of inhibition of E2 production during the 5 days of administration, with a negative feedback causing an increase in the LH:FSH ratio, much like the response to clomiphene. Because letrozole is short-acting, the problems of thick cervical mucus or a thin endometrium associated with clomiphene have not been reported with letrozole; however E2 levels are usually lower at ovulation. Pregnancy rates are comparable or better than those with clomiphene alone and there is a reduced incidence of multiple pregnancies.
d L i f l n e s t y e M a n a g e m n e t

Particularly in women who are clomiphene-resistant, weight loss will often ameliorate the situation. In overweight women it is important to ensure that abnormalities in glucose and lipid metabolism are normalized, as much as possible, before induction of ovulation. To this point there is evidence from Norman that lifestyle changes in diet and exercise may improve overall fitness and metabolic parameters, as well as ovulatory responses, even in the absence of true weight loss although there could be a redistribution of body fat with lifestyle changes.
d i T h t r o p n e r a p o y

HMG dosage; if not, increase HMG by 50% for 3 days.

4

Repeat step 3 until estradiol doubles. Perform ovarian scan every 23 days until the dominant follicle is = 14 mm. Perform daily ultrasonography until the follicle is = 18 mm. Stop HMG and perform postcoital test. Twenty-four hours later give 10,000 IU of HCG. If the postcoital test result is poor, perform intrauterine insemination.

Gonadotropin therapy is indicated for ovulation induction when estrogen levels are low. Low serum E2 levels (usually < 30 pg/mL) or lack of withdrawal bleeding after progestogen administra-tion signifies a state that will be unresponsive to oral therapies (clomiphene, letrozole) that are dependent on a negative feedback system. Apart from this indication in usually amenorrheic women, it is appropriate to use gonadotropins in clomiphene/letrozole failures, rather than on the basis of persistent anovulation or the inability to conceive after severe cycles (four to six) ovulatory cycles. Because each woman responds individually to the dosage of gonadotropinseven the same woman in different treatment cyclesit is essential to monitor treatment carefully with frequent measurement of estrogen levels and ovarian ultraso-nography.
i l i S y p e r s t m u t n n y d r o m o e a

HCG, human chorionic gonadotropin; HMG, human menopausal gonadotropin.

G d i R l i o n o p n e a a t r e s n g H o r m o n o

Although enlarged ovaries are frequently encountered after gonadotropin administration, the incidence of significant ovarian hyperstimulation syndrome (OHSS) occurs in approximately 0.5% of women receiving gonadotropin. OHSS can be life-threatening, causing massive fluid shifts, ascites, pleural effusion, electrolyte disturbances, and thromboembolism. The cause has not been completely elucidated but is related to the large cystic ovaries, high E2 levels and the ovarian elaboration of sub-stances such as VEGF, which increase vascularity and vascular permeability. OHSS has been classified by several investigators into mild, moderate, and severe forms.
U

Perform baseline ultrasonography of ovaries. Administer HMG, 150 IU/day for 35 days. Repeat estradiol measurement. If level has doubled, continue same

An alternative to administration of HMG is GnRH treatment. Because continuous administration of GnRH will saturate the receptors and thus inhibit gonadotropin release to induce ovulation, GnRH needs to be administered in a pulsatile manner at intervals of 1 to 2 hours Because GnRH is a peptide, it cannot be administered orally, and the two routes of administration in current use are intravenous and subcutaneous. A greater amount of drug must be administered by the subcutaneous route than by the intravenous route; however, the subcutaneous route avoids use of an intravenous catheter with its accom-panying problems. The medication is administered by means of a small portable pump, which is usually worn attached to an article of clothing. Because these medications are expensive, endoscopic partial ovarian destruction with electrocautery or laser has also been used by several groups to treat women with polycystic ovaries who do not ovulate with clomiphene citrate Ovarian wedge resection was previously used to induce ovulation in women with PCOS before ovulation-inducing drugs became available. However, severe postoperative adhesion formation often occurred, and this technique should no longer be used. To avoid this problem, partial ovarian destruction with electrocauterization or laser ablation of multiple sites has been performed. laparoscopic technique has resulted in a high rate of spontaneous ovulation and pregnancy. Even the women who do not ovulate spontaneously after this therapy usually ovulate when treated with clomiphene citrate, which was ineffective before partial ovarian destruction.

e a

o t

p a

Nevertheless ovulation induction in women with PCOS should still be a medical treatment, particularly with the use of adjuncts, if necessary. Ovarian electrocautery should be reserved for those patients who have difficulties with gonadotropin stimulation (failure of dominant follicle selection or hyperstimulation risk).
C f I f i l a u s e o e r t i t

If the only abnormal finding in the infertility investigation is the presence of IUA, the prognosis for conception after hysteroscopic lysis of the adhesions is good.
m o y m l

All gynecologists who care for infertile couples should understand how to interpret a semen analysis as well as how to offer a prognosis for a disorder of abnormal semen. Intrauterine insemination has been used to treat oligospermia, as well as abnormalities of semen volume or viscosity. The technique of intrauterine insemination of sperm following their separation from the semen by centrifugation should be used to treat mild to moderate abnormalities in the semen analysis and unexplained infertility. This procedure is associated with higher pregnancy rates if it is combined with COH than when used in natural ovulatory cycles. Intrauterine insemina-tion is also of benefit to women with cervical stenosis, such as that sometimes found following cervical conization. Ideally, insemination should take place on the day of or 1 day before ovulation. It is advisable to utilize urinary LH enzyme-linked immunosorbent assay (ELISA) kits to determine the optimal date to perform insemination since the urinary LH peak occurs on the day prior to ovulation. Insemination should be scheduled for the morning after LH is initially detected in an afternoon urine specimen. Separation of sperm from the seminal fluid by double centrifugation, the swimup technique, or use of a density gradient should be performed before intrauterine insemination. Intrauterine insemination of seminal fluid can produce severe uterine cramps as a result of prostaglandin release. Some couples, particularly those whose male partner has azoospermia, may choose to utilize donor sperm insemination. If they do so, the attitudes of both partners regarding the use of donor semen and the stability of the marriage need to be thoroughly discussed before the procedure is performed. Donors from sperm banks are carefully screened for infectious diseases, and all semen samples are quarantined for at least 6 months because of the long time it takes for positive antibodies to HIV to appear after infection.
C f I f i l e a u s e s o e r t i t i A d n h a u t e r n e e s i n o s y

Congenital uterine defects rarely cause infertility, and the uterine anomalies associated with maternal ingestion of diethylstil-bestrol (DES) have not been shown in randomized studies to be a cause of infertility. It is also difficult to assess the effect of leiomyomas on conception, since so many women with leiomyomas have no difficulty conceiving. Nevertheless, it is plausible that cervical myomas could cause distortion of the endocervix, interfering with normal sperm transport, and that some submucous leiomyomas may interfere with sperm transport or normal implantation of the blastocyst. There is evidence that certain myomas (depending on location) can increase the risk of abortion. Large intrauterine leiomyomas can also occlude the interstitial portion of the oviduct and prevent normal sperm transport. If no other cause of infertility is found and myomas of moderate size and position that may interfere with sperm transport are present, then a myomectomy is justified.
b e r c u s i o s

A.

If the HSG reveals findings consistent with pelvic tuberculosis, then endometrial biopsy and culture should be performed to confirm the diagnosis. The radiographic features of pelvic tuberculosis that are virtually diagnostic of the disease include (1) calcified lymph nodes or granulomas in the pelvis (2) tubal obstruction in the distal isthmus or proximal ampulla, sometimes resulting in a pipe-stem configuration of the tube proximal to the obstruction (3) multiple strictures along the course of the tube (4) irregularity to the contour of the ampulla (5) deformity or obliteration of the endometrial cavity without a previous curettage Appropriate antituberculosis medication should be initiated, but women with pelvic tuberculosis should be considered sterile, as pregnancies after therapy are rare. Tubal reconstructive surgical procedures are therefore pointless. If tuberculosis is present in the oviduct but not the uterus, pregnancies have been reported following IVF.
l C f I f i l a u s e s o e r t i t

Most women with IUA have had a previous curettage of the uterine cavity, most often during or shortly following a pregnancy.

If both proximal and distal obstructions of the oviduct exist, the damage to the oviduct is usually so extensive that the oviduct cannot function normally. Therefore, although it is possible to achieve tubal patency after

surgical repair of a tube with both proximal and distal blockage, subsequent intrauterine pregnancy is uncommon. Therefore, surgical reconstruction should not be performed in such instances.
A D i l T b l D i u e a s a t a s s

Fragments of fimbriae not readily identified Periovarian or peritubular adhesions without fixation, minimal cul-de-sac adhesions Absence of a rugal pattern on preoperative hysterogram
S e v e r e

HSG will determine whether the tubal obstruction is complete or partial, the size of the distal sacculation, and the appearance of the mucosal folds and rugal pattern of the endosalpinx Laparoscopy will assist in determining the size of the hydrosalpinx, the amount of muscularis, and the thickness of the wall of the oviduct after distention with dye. Laparoscopic examination will determine whether pelvic adhesions are present and the extent of such adhesions. Women with fimbrial obstruction are not a homogeneous group, and the prognosis for intrauterine pregnancy following distal tubal reconstruction is related to the extent of the disease process Therefore, it is important to perform both HSG and laparoscopy before surgical reconstruction to provide an individualized prognosis. tubal reconstruction with the degree of tubal damage according to the severity of five factors (1) extent of adhesions (2) nature of adhesions (3) diameter of the hydrosalpinx (4) appearance of the endosalpinx (5) thickness of the tubal wall.
C l i f i i f h E f T b l D i i h D i l F i b i l O b n o n o u e a s s a t t e

Large hydrosalpinx greater than 30 mm diameter No fimbriae Dense pelvic or adnexal adhesions with fixation of the ovary and tube to the broad ligament, pelvic sidewall, omentum, or bowel Obliteration of the cul-de-sac Frozen pelvis (adhesion formation so dense that limits of organs are difficult to define)
B
P i l T b l

Absent or small hydrosalpinx less than 15 mm diameter Inverted fimbriae easily recognized when patency is achieved No significant peritubal or periovarian adhesions Preoperative hysterogram reveals a rugal pattern
M o d e r a t e

Hydrosalpinx 1530 mm in diameter

If no dye reaches the oviduct during an HSG, the diagnosis of proximal tubal blockage is likely. However, since spasm of the intrauterine portion of the oviduct can occur, the diagnosis cannot be confirmed unless laparoscopy is performed with general anesthesia. Here at least half of the time the tube is found to be patent Laparoscopy also allows examination of the distal portion of the oviduct, which cannot be visualized radiographically if there is proximal blockage. Proximal tubal blockage is most commonly due to residual damage after infection, but it can be due to plugs of material or endometriosis The use of microsurgery has improved intrauterine rates for proximal tubal disease. Before the use of microsurgery, tubal intrauterine blockage was treated by reimplantation of the patent portion of the oviduct into the endometrial cavity The surgical treatment of a proximal tubal blockage has now been replaced in most centers by the use of transcervically placed probes, catheters, or balloons, which are placed under fluoroscopic or hysteroscopic guidance in an outpatient setting with or without local anesthesia and sedation
j i T u n c t e h e r a p y v

10

Adjunctive procedures for surgical tubal reconstruction previously included prophylactic antibiotics, intraperitoneal corticosteroids, postoperative hydrotubation, and placement of tubal stents. It is important to stress surgical technique, attention to hemostasis and irrigation of blood and debris away from the surgical site with Ringers' lactate solution. The only barriers currently used with some efficacy are Interceed (to be used only in areas which are dry and not bleeding) and barriers impregnated with hyaluronic acid (Seprafilm).
i i m e t r s o s

appears to be no benefit from postoperative danazol or GnRH agonist treatment

U
l n e

Operative treatment of endometriosis has for many years included the use of electrocautery as well as microsurgical techniques
i d I f i l p n e e r t i t a

Mild Endometriosis An inflammatory/immune reaction occurs in endometriosis that affects fertility status even if the process is mild If only mild endometriosis is found at the time of laparoscopy and no other cause of infertility is present, then it is advisable to treat these individuals with controlled ovarian hyperstimulation and intrauterine insemination similar to the treatment of unexplained infertility. They found that the relative likelihood of pregnancy with the use of clomiphene citrate supraovulation was 2.9 times that of women who re-ceived no treatment. Use of danazol was associated with the same likelihood of pregnancy as occurred with no treatment. Moderate Endometriosis If pelvic adhesions that cannot be lysed at the time of lapa-roscopy or ovarian endometriomas larger than 1 cm in diameter are present, medical therapy will not cause sufficient regression to improve fertility rates, and surgical treatment should be undertaken. For women with moderate disease without ovarian endometriomas and minimal adhesions that can be cut at the time of laparoscopy, no evidence indicates that medical treatment improves fertility rates compared with no treatment. The use of danazol, GnRH agonists, progestins, or oral contraceptives has not been shown to increase fertility rates compared with observation without treatment. Severe Endometriosis Conservative operative resection of endometriosis should be performed for women with infertility and moderate or severe disease with adhesions that cannot be cauterized or lysed at the time of laparoscopy or those with endometriomas more than 1 cm in diameter. Preoperative treatment with danazol or GnRH agonists for 6 weeks to 3 months is advised by some authorities to facilitate the surgical resection, but there

diagnosis of unexplained infertility should be made and treatment initiated with COH and appropriately timed preovulatory IUI with a sample of freshly prepared, recently ejaculated sperm or IVF. COH should be performed with either clomiphene citrate or HMG. Insemination is best performed on the day prior to spontaneous ovulation, on the morning following the day that LH is initially detected in a random urine specimen, or 36 hours after intramuscular HCG is given to induce ovulation.
F i l i o e r t z a t i

Technique of IVF-ET is now being widely used to treat infertility Rate of pregnancy after IVF is directly related to the number of embryos placed in the uterine cavity, nearly all IVF clinics currently utilize some form of ovarian hyperstimulation to increase the number of oocytes obtained at the time of follicle aspiration. Two main advantages for performing IVF with eggs collected from the dominant follicle in a normal, unstimulated ovulatory cycle. First, the substantial cost of administering gonadotropin and additional days of monitoring that are necessary in stimulated cycles are avoided. Second, more aspiration cycles can be performed in the same time period Originally, oocyte retrieval was done by laparoscopic visualization. Follicle aspiration is now being performed routinely through the vagina into the cul-de-sac with sonographic guidance of needle placement. A few hours after egg retrieval, sperm that has been separated from semen are added to the culture medium. About 18 hours later the oocytes are observed to determine if fertilization has occurred. The oocytes that are fertilized are then cultured for an additional 48 to 96 hours, and from one to four normally cleaving embryos are then placed into the uterus of the patient in a sterile environment without the use of general anesthesia Embryo placement is performed through a small catheter placed through the cervical canal. With the development of sequential culture media it has become possible to allow embryos to develop in vitro to the blastocyst stage, 5 days after fertilization, prior to transfer into the endometrial cavity.

11

A modification of IVF, called can be used if the infertile woman has functioning oviducts. With this technique both oocytes and sperm are placed into the oviduct through a catheter at the time of laparoscopy or minilaparotomy. Although IVF, embryo culturing, and embryo transfer into the uterus are avoided by this technique, ovarian hyperstimulation and laparoscopy are still required. and Modifications of GIFT include With ZIFT the oocytes are fertilized in vitro and transferred 24 hours later. Tubal embryo transfer (TET) is similar to ZIFT except the embryos are transferred 8 to 72 hours after fertilization Cryopreservation of embryos that have undergone IVF is being used in most assisted reproductive centers. Cryopreservation allows embryos that cannot be immediately transferred to the woman to be stored for future use. If more than four eggs are fertilized in a given cycle, the excess embryos can be frozen if they are of good quality.
g a m n a r a p a i e t e i t o n t a r n s e r

) ,

developing a clinical pregnancy in each ovulatory cycle. In about half of fertile couples attempting to conceive the woman will become pregnant in 3 months, 75% in 6 months, and 90% at the end of 1 year. Infertile couples who conceive do not have higher rates of spontaneous abortion or perinatal mortality than age-matched control subjects. In the United States approximately 10% to 15% of cases of infertility are caused by anovulation, 30% to 40% by an abnormality of semen production, 30% to 40% by pelvic disease, and 10% to 15% by abnormalities of sperm transport through the cervical canal. About 10% to 20% of cases are unexplained. The primary diagnostic tests for infertility are documentation of ovulation, semen analysis, and hysterosalpingogram (HSG). The basal body temperature (BBT) increases when circulating levels of progesterone increase, and a sustained increase of BBT occurs following ovulation. A sustained rise in BBT or a serum progesterone level greater than 5 ng/mL is presumptive evidence of ovulation. A midluteal-phase serum progesterone level above 10 ng/mL is an indication of adequate luteal function. A high percentage of fertile men will have at least one abnormal parameter in their semen analysis. In women with a normal HSG, a hysteroscopy is unnecessary because it will not detect additional abnormality. Other diagnostic tests for infertility, including (1) measurement of serum prolactin and TSH in ovulatory women, (2) a late luteal-phase endometrial biopsy, (3) immunologic tests to detect sperm antibodies, and (4) bacterial culture of cervical mucus and semen. There is no evidence that treatment of an abnormality in the tests just listed significantly improves pregnancy rates compared with withholding therapy. Of all the causes of infertility, treatment of anovulation results in the greatest success. When ovulation is induced with clomiphene citrate and no other causes of infertility are present, conception rates over time are similar to those

a r

a r

T F

a r

Final Couseling If intensive treatment of the infertile couple with various techniques fails to result in conception after 2 years, the couple should be informed that the chances for conception are much reduced. It is best to inform the couple of the prognosis for fertility and the duration beyond which conception should not be expected at the time of the initial consultation, and this information should be restated at subsequent visits. When the period during which conception should be expected has been exceeded, the couple should be informed that further testing and treatment are not warranted and other alternatives such as adoption should be considered. Finally, it is important for the couple to consider psychological counseling, because the prospect of permanent infertility can cause severe mental trauma
K E Y P O I N T S

In 1995 about 10% of all U.S. couples with women in the reproductive age group were infertile6.2 million women. The incidence of infertility steadily increases in women after age 30. Among fertile couples who have coitus in the week before ovulation, there is only about a 20% (monthly fecundability of 0.2) chance of

12

of a normal fertile population. Discontinuation of therapy is the major reason for the reported difference in ovulation and conception rates in anovulatory women treated with clomiphene. More than 90% of women with oligomenorrhea and 66% with secondary amenorrhea and E2 levels of 40 pg/mL or higher will have presumptive evidence of ovulation following clomiphene therapy. When conception occurs after clomiphene treatment in anovulatory women, the incidence of multiple gestation is increased to about 8%, nearly all of them being twin gestations. The incidences of clinical spontaneous abortion, ectopic gestation, intrauterine fetal death, and congenital malformation are not significantly increased. Formation of ovarian cysts is the major side effect of clomiphene treatment. About 5% to 10% of women treated with the individualized, graduated, sequential regimen of clomiphene citrate fail to ovulate with the highest dosage. Treatment of anovulation with gonadotropin effects an ovulatory rate of about 100%. The pregnancy rate per cycle with gonadotropins is similar to that following clomiphene therapy (22%). The incidence of spontaneous abortion after HMG therapy is high (25% to 35%), and clinically detectable ovarian enlargement occurs in about 5% to 10% of treatment cycles. If GnRH is used for ovulation induction it needs to be administered in a pulsatile manner at intervals of 1 to 2 hours. For women with polycystic ovaries who do not ovulate following administration of clomiphene citrate, partial ovarian destruction by electrocautery or laser through the laparoscope is effective in inducing ovulation. Pregnancy rates for oligospermia following intrauterine insemination are in the 25% to 35% range. Semen donors need to be carefully screened to be certain that they are in good health, do not have a potentially inherited disorder, and will not transmit an infectious agent in the semen.

Because antibodies to HIV may not develop for several months after infection, it is recommended that all donor insemination be performed with frozen sperm that has been stored for at least 6 months at which time negative antibodies to HIV should be observed in the donor before the sperm is used for insemination. The prognosis for fertility after tubal reconstruction depends on the amount of damage to the oviduct as well as the location of the obstruction. If both proximal and distal obstructions of the oviduct exist, intrauterine pregnancy is uncommon, and operative reconstruction should not be performed, IVF is the best therapy. Women with pelvic tuberculosis should be considered sterile, and no tubal reconstructive procedures should be attempted. IVF may be attempted if the endometrial cavity is not infected. Overall conception rates following salpingostomy are in the 30% range, with a high percentage (about one fourth) being tubal pregnancies. The pregnancy rate after salpingolysis and fimbrioplasty for partial distal obstruction is about 65%. Unlike the results of distal tubal reconstruction, the use of microsurgery has improved intrauterine pregnancy rates for proximal tubal disease. Proximal tubal obstruction is now usually treated by cannulation of the oviducts with catheters or balloons placed under hysteroscopic visualization. The benefit of second-look laparoscopy after tubal surgery has not been established. No medical therapy for endometriosis has proved to increase pregnancy rates compared with no treatment. Pregnancy rates for women with mild endometriosis can be increased with the use of controlled ovarian hyperstimulation and intrauterine insemination but not with danazol. About 65% of women with mild endometriosis and no other cause of infertility conceive without treatment. With moderate or severe disease, pregnancy rates with expectant management are 25% and 0%, respectively. Conception rates for women treated surgically have been reported to be

13

in the 50% to 60% range for those with moderate endometriosis and 30% to 40% for those with severe endometriosis. About half of infertile women with myomas conceive after myomectomy. Luteal-phase deficiency, as currently diagnosed histologically, is probably a normal biologic variant and not a true cause of infertility. No data conclusively demonstrate that the finding of antisperm antibodies in either member of the couple is a cause of infertility. In women with unexplained infertility the use of controlled ovarian hyperstimulation (COH) and intrauterine insemination (IUI) yields monthly fecundity rates of 10% to 15%. Therefore COH and IUI should be the initial treatment for women who ovulate, have patent oviducts, and whose male partner has at least 5 million motile sperm in the ejaculate. For IVF with and without ICSI the delivery rate per cycle in which ova are retrieved is as high as 40% depending on the age of the woman. The rate of pregnancy following IVF is directly related to the number of embryos placed in the uterine cavity. The pregnancy rate per cycle of IVF remains relatively constant for about six cycles after which it declines. After six cycles the cumulative pregnancy rate is about 60%. There is a high spontaneous abortion rate (about 30%) for pregnancies after IVF. If an infertile couple fails to conceive after 2 years of therapy, they should be informed the chances for conception are remote. The optimal treatment for all causes of sperm abnormalities is ICSI. With this technique, pregnancy rates per cycle are similar to that of IVF performed for other causes of infertility.

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