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e t e y t e n n c i n f p I c c o r o v e t r . a corresponding decrease occurs in the total duration of time during which she may conceive. n t t i t T F i o n a l u r a p u s r t a o a a s ..g. e o . b r r o m s u i m a e e o l s e e c o s o n f H n t r i p s e t t o . as a woman becomes older. Both older and more recent studies indicate that the percentage of infertile couples increases with increasing age of the female partner. l t c f a i c i d f n e o m r r t e e a l O t d e i e d n e t t u s v n o m 5 ( i s b h m o e v n s h a n r s s i i t i H h a . ) h d e h e T w a e i a f t e z h s o h o r t e p e u o e i n a r s s t t s s p i t s p o s e i u o r e r c n y b m r h m a o a i y b r e b b e o i p s i t i t u d d h u n r p i j y e s y d e e c c t I o i t o C m o e t i S n s I d r 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. t t t a r e e p . r h t i a i m a a t e h s l t t t i a t w o n h h y r t l l i e i y y h e t n n h n e l d t e e l d e s n s s h n e d E T x e t r s a t c i • • • • • • • • 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. o h o n t t t e t m f o m i i u u e s v c n t i u s f e t e p t w d o n e g i .( a S S S S S S u S a a Z T r r P r P T r T P r n o N T T o U a t T a o n e e y p r y a l n i E n e a e n o g s a n l l a b e o n g c n t T m p p p d g n i u d i i n n r ) x o t o n e e s t s o l t o a c f a p s f z e n b r a m E i g g g T r e o r l r e o o l a i n I a a t r c n e t n i o e a A m n l m n i u s T ( ( l a t r s o t . 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. S o u d m m e u n e n . v a c l s e . a o e b t s o a o i i n n o m e m t a s l i e b w f . n r m u c s S n x e c T e a t r e w c f a a S t a b t i u r i t o n h i y . e o s i s s a t n h m d v r d e d t s e o n a i a S i i 0 l d f u d e e e l t e i t n e S n i v o a c v n o p P v t n n l t a a a e a r c o % n o r i g s i n l n m w a ) a o n s y h i p c e i o o c o t y l i t p . v e c h t i s o f o e s e t n t n f f o o o v i c o z c e n a e s a n e d r i f o d e o o a i t y o s l r a o v u i e i v . s u l n n n e c o u t i m t m e f i l 0 n l t i h o o l m z i i d h r c a r n o e t e a l . s l r t l c r f s r i v n u f f a c l t a e i e a a t i i c o a l g c u g m n o a o f c i c t a q a u l u c l e a m n l u l n t e u d r e i y r t r l o i . y b r t y r k e - Z a P s s e I e I ( s T i l n I i a b R f p o F d S y s t a f y s e O t a t e m e r n T l O s s I r h ) d i l y t H S o l E s T ( e g r S f T m a m S T ) a e p r i c i e m o n ) p E a n e a i u T t b r r S i n s l T i f o d y ) a t b e r n e y l t o o T a a a a o I i i I u s f S x p a h e u S t t o c y h c a e e E P s D a R v G u n n t j a o h i r c h r p e t a v r a n Q l w m s s s n i t v e f r a i v o l s e e r c a e e a e p e o u c u a r s u o m g i p t r m r d e a i r l n e m e d t s e v o l a i a i a t c a d y n i l r e i i u p c r a y c u t e e t . a i t d i a O t n . I e f a . Because the occurrence of monthly ovulation decreases greatly after age 45. t r n e c e a t f t f v i o o r r z i o s e v e o f p a m e e z s o r t d p o h m e m e y b r s e f n p m v o r i a o e a f r ) l o s m l m w i i a i c t r l t . 2 . t o c s f p c o r i t g o o r c i t t i a o h c r e o e t m i c r t e g d e d g m a l i p s h n n i a b c a l e l t s a t s c e s g f l o p o d e s d r u e f t c u a r l t r n e t m n o s o s y c o e b t n o o i s e d o a d e d w a a p I r . they should be counseled to maximize the length of time during which they attempt to conceive. l a r z i f o f m m . a t c i n f o m s m t e n i n s e e t o a e y b a s d h n e a u a s m o w i r e h h p i p g n o e t a f e l n t d r a a o t l n e a a r o o ( m i l c w n a . x n u c a e c l o a r m n m c n f a u d e 1 n u a r a b n e b i s a r w p a r i s c n i i e p l t i n d t l c y u l o m i a h y c . n h e o i m s t l n r d b l o i n e h e f s e a s o x e f t e t f s i a o a h i n r s n i f s h . if couples intend to have children. Group includes those with hypofertility due to presumed causes (e. l i e n s o e f a i f r i s t h u r n o a b a s c s e n . c u t o i a l n r S p e r i n m f e r t i l i y t o a a o i ( ( p R n n o o l r s b o e l t b t p s i s r t c n o p i a r o t r u r e u r v e e v u d b t a s o c i a s c t e o t r t i l n i v u r n . r r o e n g h r i g u m l Z t i f n r e e o m t n s e s e f s i y i c d e n t a r e l y r . 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. r a e c u c e t a n b e a . 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. Because a woman's reproductive life span is limited to a certain number of years. g p l o e l a n e u ) i o h u c e d n .

Therefore. as has in vitro fertilization. which usually occurs 15 to 20 minutes after ejaculation. a serum progesterone level should be measured in the midluteal phase to provide indirect evidence of ovulation as well as normal luteal function. 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. Because the egg disintegrates less than a day after it reaches the ampulla of the oviduct. 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. a serum progesterone level above 10 ng/mL is indicative of adequate luteal function. All couples should have a complete history taken. Semen should not be exposed to marked changes in temperature. Ovulation most commonly occurs on the day following the detection of LH in a random specimen (12 to 24 hours later). Sperm motility begins to decline 2 hours after ejaculation.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. Sperm morphology is an extremely important parameter. 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). which contains urine formed during the prior night. Using strict criteria (Kruger) only approximately 15% or more of the sperm in an ejaculate may be considered normal. with sublingual placement of a special thermometer with gradients between 96° and 100° F. and if collected at home during cold weather. The degree of sperm motility should be determined as soon as possible after liquefaction. Husband has oligospermia. 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. Peak levels of LH occur 1 day before ovulation. s 3 . and a physical examination. I I S A l e m n e n a y s i . • Although in the normal luteal phase serum progesterone levels vary in a pulsatile manner. I . including a sexual history. and it occurs on the day when LH is detected in the first morning specimen. It is best to collect the specimen in a clean (not necessarily sterile). collection should take place in the location where the analysis will be performed. because the initial fraction contains the greatest density of sperm. • Measurement of daily BBT also provides indirect evidence that ovulation has taken place. • If the woman is having regular menstrual cycles. When ovulation is more precisely determined as with luteinizing hormone (LH) monitoring (see the following discussion). it is preferable to have sperm in the oviduct prior to the arrival of the oocyte. treatment with controlled ovarian hyperstimulation and intrauterine insemination has been shown to increase fecundability compared with no treatment. which is correlated to fertilizing ability. Ideally. because frequent ejaculation lowers seminal volume and occasionally the sperm count in some individuals. 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. and it is best to examine the specimen within this time period. • • • • • • • • • • • • • Male partner should be advised to abstain from ejaculation for 2 to 3 days before collection of the semen sample. intercourse should occur for 2 consecutive days around the LH surge. daily intercourse for 3 consecutive days at midcycle should be encouraged. 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. the specimen should be kept warm during transport to the laboratory. It is important that the entire specimen be collected. • 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. The BBT graph also provides information concerning the approximate day of ovulation and duration of the luteal phase. • Couples with unexplained infertility. 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. After this initial evaluation. for such women direct or indirect measurement of progesterone is unnecessary until after therapy is initiated. The BBT should be taken shortly after awakening only after at least 6 hours of sleep and prior to ambulating. widemouthed jar after masturbation.

• • 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. which is important to note if there were illness at that time. Also the semen profile reflects sperm production. 4 1 4 S A l i N l R f V e m n e n a y s s F i d i n n g a C u 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 a e : o r m a e e r n e c e a l e - - Volume pH Viscosity - 1.2 <3 (Scale 0–4) Sperm concentration >20 million mL Total sperm number >40 million ejaculate Percent motility >50% Forward progression >2 (scale 0–4) Normal morphology >50% normal >30% normal >14% normal Round cells <5 million mL Sperm agglutination < (Scale 0–3) T b l 4 1 5 C f S A b l i a e a u s e s o e m n e n o r m a t i e - - F i d i - n n g a C u s Abnormal count Azoospermia Klinefelter's syndrome or other genetic disorders Sertoli-cell-only syndrome Seminiferous tubule or Leydig cell failure Hypogonadotrophic hypogonadism Ductal obstruction.5–5. including androgen receptor defects Extraneous cells Abnormal viscosity e s u s 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 e 4 . which occurred 3 months earlier. including Young's syndrome Varicocele Exogenous factors Oligozoospermia Genetic disorder Endocrinopathies.0 mL >7.

• Cystic fibrosis screening is currently recommended in all women. Finally any symptoms suggestive of endocrine disorders should be solicited (weight changes. hysteroscopic tubal cannulation and other adjunctive procedures may be indicated on an individual basis. If an abnormality is found in one of the first two noninvasive diagnostic procedures (documentation of ovulation and semen analysis). 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. Infections disease screening (for chlamydia and gonorrhea) is carried out routinely in most practices at the time of the Pap smear. only a complete blood count (CBC). and most importantly the history of age of menopause in female family members. 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. l i e o a s p n o g r y s t r g a F i d i n n g a C u s e I V H . drugs. the overall prognosis is reduced. HIV. 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. • Family history should be explored for genetically related illnesses. once FSH has been elevated in a given cycle. • Healthy asymptomatic woman. and assessment of the vagina and cervix. y c a a c d e V A . breast secretion. If a hydrosalpinx is seen at HSG. A water-soluble contrast medium enables better visualization of the tubal mucosal folds and vaginal markings than does an oil-based medium. which is the pool of viable oocytes remaining in the ovary. 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 1 5 U / a e s o v e r m m L a r b a n o r m a l l 2 0 i u U / L i l l b v a e s o v e r m m a r e p a r t u r y u i l p r o n g o s t a l . doxycycline should be continued for 1 week. • Women older than 35. and tobacco. and even if abnormalities are present in women with regular ovulatory cycles. it should be treated before proceeding with the more costly and invasive procedures. Further infectious disease screening (syphilis. suggesting decreased ovarian reserve. hepatitis. treatment with thyroid replacement or dopamine agonists e a a 5 . unless there is a history or findings suggestive of tubal disease If these initial diagnostic tests are normal. birth defects.) is warranted only on a selective basis and is required for all couples undergoing insemination or IVF. but this recommendation is not universally followed. 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.). • Physical exam should focus on extremes of body mass. skin changes. However. 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). neither a dilation and curettage nor hysteroscopy should be routinely performed. The procedure can also determine whether salpingitis isthmica nodosa is present in the inter-stitial portion of the oviduct. blood type. if disease is present. 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. and rubella status are needed together with a Pap smear obtained within 12 months of the previous test. • If women with anovulation have hypothyroidism or hyperprolactinemia. abnormal pain on abdominal or pelvic exam. the more uncomfortable and costly hysterosalpingography (HSG) should be performed in the follicular phase of the next cycle. 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. RH. thyroid size. skin changes. Diagnostic laparoscopy may be considered to detect the presence of peritubal adhesions. V l • • These tests are usually normal. etc. etc. A M d m W m n . serum follicle-stimulating hormone (FSH) and estradiol (E2) should be obtained on cycle day 2 or 3. .• 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 . • • • • • • • • • although FSH levels tend to fluctuate from cycle to cycle.

GnRH is then released in a normal manner. E2 levels continue to increase. thereby blocking the negative feedback of endogenous estrogen. or a surgical procedure such as vasectomy reversal. Men with these antibodies have been treated with corticosteroid therapy and sperm-washing techniques. injury. 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. and the negative feedback on the hypothalamic-pituitary axis causes a decrease in FSH and LH. This synthetic. 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. stimulating FSH and LH. the exponentially rising level of E2 from the dominant e u m 6 . particularly those who have had testicular infection. urinary gonadotropins (HMG and other more FSHenriched preparations).B L l D f i i • • 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. serum levels of LH and FSH rise. About 5 to 9 days (mean 7 days) after the last clomiphene citrate tablet has been ingested. has been shown to increase the incidence of multiple gestations. similar to the change seen in the late follicular phase of a normal ovulatory cycle. 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. dopamine agonists are an effective means of inducing ovulation l n U a p a r e s m a r e a l t i c u y U r e a p a s m a r e a l t i c u u y m M p a o c l s m h f y a . weak estrogen acts by competing with endogenous circulating estrogens for estrogen-binding sites on the hypothalamus. • if conception occurs after treatment with either ovulation induction or tubal reconstructive surgery. I y c • A. as well as when combined with IVF and GIFT. accompanied by a steady increase in serum E2 After ingestion of clomiphene citrate is discontinued. 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. 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. During the days the drug is ingested. Management of Causes of Infertility • A l n o v u t i o n a u e a t e n e c . 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. 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. • • 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. C M o m i n i s M e r m e n t a n s i t r a t . IVF with or without intracytoplasmic sperm injection (ICSI) should be recommended. if anovulation is due to hyperprolactinemia. . which in turn cause oocyte maturation with increased E2 production. recombinant FSH recombinant LH and colleagues and coworkers and associates gonadotropin-releasing hormone (GnRH). • • I f Autoimmunity to sperm in both semen and serum has been found in some infertile men. . • 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.

This is because of gastrointestinal effects (nausea. and finally 250 mg for 5 days. However. The mechanism of action is that of inhibition of E2 production during the 5 days of administration. in the next cycle 250 mg is given daily for 5 days. the problems of thick cervical mucus or a thin endometrium associated with clomiphene have not been reported with letrozole. Reproductive Endocrinology) as well as directly stimulating the ovary. stimulation and further enlargement of the cyst may occur. from a practical standpoint it is unusual to use doses higher than 150 mg. indicating the value of the individualized sequential treatment regimen. However. 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 R o s i g • • In insulin-resistant patients with PCOS. With this regimen if ovulation does not occur with the 50-mg dose. If ovulation is induced with any of these dosages.follicle has a positive feedback effect on the pituitary or hypothalamus. the dosage of drug is increased in the next treatment cycle to 100 mg/day for 5 days. Pregnancy rates are comparable or better than those with clomiphene alone and there is a reduced incidence of multiple pregnancies. producing a surge in LH and FSH. which is used for diabetes. with a negative feedback causing an increase in the LH:FSH ratio. the diabetic drugs (thiadolazimediones) may induce ovulation by improving the insulinhormone axis as well as through direct effort on the ovary. the same dosage of clomiphene citrate is ingested in subsequent cycles until conception occurs. ***Various treatment regimens have been advocated for the use of clomiphene citrate. Its principal role is in reducing hepatic glucose production and thus commensurately decreasing hyperinsulinemia. Typical dose of metformin is 1500 mg/day. Most start with an initial dosage of 50 mg per day for 5 days beginning on the fifth day of spontaneous or induced menses. it also has a direct effect on the ovary. 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. If ovulation fails to occur with the initial dosage. If ovulation does not occur with 250 mg. If presumptive evidence of ovulation occurs with this dosage. and an additional one fifth did so with the 100 mg/day dosage. the woman is maintained on her individualized ovulatory dosage until conception occurs. However. Its mechanism of action in inducing ovulation is both through reducing insulin resistance (and thereby affecting gonadotropins and androgens (see Chapter 4 . 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. increasing dosage regimen has proven to be effective with a minimum of side effects. Cysts can occur in any treatment cycle with any dosage. graduated. which is no longer available). however E2 levels are usually lower at ovulation. Because letrozole is short-acting. d L i f l n e s t y e M a n a g e m n e t e o e 7 . and 1 week after the last tablet has been ingested. It is preferable to use longacting tablets (XR or ES) in 500. ***Some data suggest that in women with elevated levels of dehydroeipandrosterone sulfate (DHEA-S). checking chemistry blood levels after 3 months of metformin is good practice. particularly when adjuncts are available such as metformin or switching to letrozole. However. use of low doses of dexamethasone may enhance the ovulationinducing effect of clomiphene. biguanine. It should be begun. and the incidence is not increased with the higher dosages of drug. If ovulation does not occur with 100 mg/day in subsequent cycles. much like the response to clomiphene. they will regress spontaneously without therapy. however. the dosage is sequentially increased to 150 mg. 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. There is only a small risk of hepatic enzyme changes (unlike troglitazone. Clinically palpable ovarian cysts occur in about 5% of women treated with clomiphene citrate but in less than 1% of treatment cycles. and women also should be reminded not to drink alcohol heavily. However. only at 500 mg and titrated up over several weeks. The cysts usually range in size from 5 to 10 cm and do not require surgical excision as they nearly always regress spontaneously. which usually results in ovulation and luteinization of the follicle. a sequential. 5000 IU of HCG is given to increase the chances of inducing ovulation by simulating the LH surge. These drugs have also been added to clomiphene therapy. this therapy should be reserved for short-term use under special circumstances.and 750-mg tablets and to ingest them all at the same time at dinner. about one fourth of all women who ovulated or conceived did so following treatment with a higher dosage regimen. There is the most experience with letrozole. but if additional clomiphene citrate is given and further gonadotropin release is induced. o l L e t r o z • • • • W i h e g t a Aromatase inhibitors are efficacious as primary agents for ovulation induction. but there is also a tendency for weight gain with long-term treatment. ***If cysts are present. 200 mg. vomiting) Lactic acidosis is a very rare complication that occurs pri-marily in older individuals.

5% of women receiving gonadotropin. O i v a r “ S n a H ” T P l i h H M l G d i ( H M G p p e a e r t t m n e t r o o t c o w t u m a n n e o p a u a s o n a o t r o p . and the two routes of administration in current use are intravenous and subcutaneous. o G n a • • • Gonadotropin therapy is indicated for ovulation induction when estrogen levels are low. HMG. even in the absence of true weight loss although there could be a redistribution of body fat with lifestyle changes.• • 6 • Particularly in women who are clomiphene-resistant. moderate. and this technique should no longer be used. In overweight women it is important to ensure that abnormalities in glucose and lipid metabolism are normalized. Twenty-four hours later give 10. 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. 1 - n ) - e 8 . causing massive fluid shifts. 8 . which is usually worn attached to an article of clothing. 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 . it is appropriate to use gonadotropins in clomiphene/letrozole failures. high E2 levels and the ovarian elaboration of sub-stances such as VEGF. partial ovarian destruction with electrocauterization or laser ablation of multiple sites has been performed. Stop HMG and perform postcoital test. severe postoperative adhesion formation often occurred. Because each woman responds individually to the dosage of gonadotropins—even the same woman in different treatment cycles—it is essential to monitor treatment carefully with frequent measurement of estrogen levels and ovarian ultraso-nography. The cause has not been completely elucidated but is related to the large cystic ovaries. The medication is administered by means of a small portable pump. human menopausal gonadotropin. and severe forms. perform intrauterine insemination. however. 3 . human chorionic gonadotropin. Because continuous administration of GnRH will saturate the receptors and thus inhibit gonadotropin release to induce ovulation. if not. U • • • Perform baseline ultrasonography of ovaries. continue same • An alternative to administration of HMG is GnRH treatment. A greater amount of drug must be administered by the subcutaneous route than by the intravenous route. i l i S y p e r s t m u t n n y d r o m o e a HCG. Because these medications are expensive. . letrozole) that are dependent on a negative feedback system. Even the women who do not ovulate spontaneously after this therapy usually ovulate when treated with clomiphene citrate. To avoid this problem. • • • • • • • Although enlarged ovaries are frequently encountered after gonadotropin administration. the incidence of significant ovarian hyperstimulation syndrome (OHSS) occurs in approximately 0. pleural effusion. rather than on the basis of persistent anovulation or the inability to conceive after severe cycles (four to six) ovulatory cycles. increase HMG by 50% for 3 days. the subcutaneous route avoids use of an intravenous catheter with its accom-panying problems. 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. 150 IU/day for 3–5 days. electrolyte disturbances. d i T h t r o p n e r a p o y HMG dosage. If the postcoital test result is poor. which increase vascularity and vascular permeability. weight loss will often ameliorate the situation. as well as ovulatory responses. To this point there is evidence from Norman that lifestyle changes in diet and exercise may improve overall fitness and metabolic parameters. before induction of ovulation. Apart from this indication in usually amenorrheic women. GnRH needs to be administered in a pulsatile manner at intervals of 1 to 2 hours Because GnRH is a peptide. Administer HMG. which was ineffective before partial ovarian destruction. as much as possible. Repeat estradiol measurement. it cannot be administered orally. laparoscopic technique has resulted in a high rate of spontaneous ovulation and pregnancy. Perform ovarian scan every 2–3 days until the dominant follicle is = 14 mm. 5 . and thromboembolism. Perform daily ultrasonography until the follicle is = 18 mm. 4 Repeat step 3 until estradiol doubles. ascites. OHSS can be life-threatening. However. OHSS has been classified by several investigators into mild.000 IU of HCG. 7 . If level has doubled. 2 .

It is also difficult to assess the effect of leiomyomas on conception. If they do so. If tuberculosis is present in the oviduct but not the uterus. • 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. If no other cause of infertility is found and myomas of moderate size and position that may interfere with sperm transport are present. Nevertheless. it is plausible that cervical myomas could cause distortion of the endocervix. particularly with the use of adjuncts. 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. the prognosis for conception after hysteroscopic lysis of the adhesions is good. 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. although it is possible to achieve tubal patency after n y 9 . Ovarian electrocautery should be reserved for those patients who have difficulties with gonadotropin stimulation (failure of dominant follicle selection or hyperstimulation risk). Insemination should be scheduled for the morning after LH is initially detected in an afternoon urine specimen. 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. There is evidence that certain myomas (depending on location) can increase the risk of abortion. 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. Donors from sperm banks are carefully screened for infectious diseases. but women with pelvic tuberculosis should be considered sterile. the damage to the oviduct is usually so extensive that the oviduct cannot function normally. or use of a density gradient should be performed before intrauterine insemination. 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. as pregnancies after therapy are rare. interfering with normal sperm transport. Intrauterine insemination has been used to treat oligospermia. Some couples. Ideally. and that some submucous leiomyomas may interfere with sperm transport or normal implantation of the blastocyst. if necessary. This procedure is associated with higher pregnancy rates if it is combined with COH than when used in natural ovulatory cycles. u T • A. Intrauterine insemina-tion is also of benefit to women with cervical stenosis. Intrauterine insemination of seminal fluid can produce severe uterine cramps as a result of prostaglandin release. then a myomectomy is justified. since so many women with leiomyomas have no difficulty conceiving. most often during or shortly following a pregnancy. Large intrauterine leiomyomas can also occlude the interstitial portion of the oviduct and prevent normal sperm transport. 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. as well as abnormalities of semen volume or viscosity. m o y m l B L e i . particularly those whose male partner has azoospermia. then endometrial biopsy and culture should be performed to confirm the diagnosis. Therefore. the swimup technique. Tubal reconstructive surgical procedures are therefore pointless. • If both proximal and distal obstructions of the oviduct exist. l C f I f i l a u s e s o e r t i t U t e r I n i t n r T u a b a • Most women with IUA have had a previous curettage of the uterine cavity. Separation of sperm from the seminal fluid by double centrifugation. b e r c u s i o s M a l e n y C . pregnancies have been reported following IVF. such as that sometimes found following cervical conization. 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. o • • • • • • • • • • • 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. may choose to utilize donor sperm insemination. 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.• Nevertheless ovulation induction in women with PCOS should still be a medical treatment. If the HSG reveals findings consistent with pelvic tuberculosis. insemination should take place on the day of or 1 day before ovulation.

and the prognosis for intrauterine pregnancy following distal tubal reconstruction is related to the extent of the disease process • Therefore. 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 B l r o x m a u c a k g . since spasm of the intrauterine portion of the oviduct can occur.surgical repair of a tube with both proximal and distal blockage. 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. pelvic sidewall. However. the amount of muscularis. 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 x t e t s s e w t s a t m r s t r u c t i o M i l d o n a a c a C A . surgical reconstruction should not be performed in such instances. 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. 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. • Women with fimbrial obstruction are not a homogeneous group. 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. and the thickness of the wall of the oviduct after distention with dye. omentum. the size of the distal sacculation. the diagnosis cannot be confirmed unless laparoscopy is performed with general anesthesia. d o e a 10 . it is important to perform both HSG and laparoscopy before surgical reconstruction to provide an individualized prognosis. catheters. subsequent intrauterine pregnancy is uncommon. or balloons. Proximal tubal blockage is most commonly due to residual damage after infection. which cannot be visualized radiographically if there is proximal blockage. the diagnosis of proximal tubal blockage is likely. 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. Therefore. • 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 15–30 mm in diameter If no dye reaches the oviduct during an HSG. • 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. 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. • Laparoscopic examination will determine whether pelvic adhesions are present and the extent of such adhesions. and the appearance of the mucosal folds and rugal pattern of the endosalpinx • Laparoscopy will assist in determining the size of the hydrosalpinx. • 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 .

no evidence indicates that medical treatment improves fertility rates compared with no treatment. 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. oocyte retrieval was done by laparoscopic visualization. recently ejaculated sperm or IVF. COH should be performed with either clomiphene citrate or HMG. then it is advisable to treat these individuals with controlled ovarian hyperstimulation and intrauterine insemination similar to the treatment of unexplained infertility. • The use of danazol. • Preoperative treatment with danazol or GnRH agonists for 6 weeks to 3 months is advised by some authorities to facilitate the surgical resection. postoperative hydrotubation. A few hours after egg retrieval. intraperitoneal corticosteroids. or oral contraceptives has not been shown to increase fertility rates compared with observation without treatment.• • • Adjunctive procedures for surgical tubal reconstruction previously included prophylactic antibiotics. 5 days after fertilization. The oocytes that are fertilized are then cultured for an additional 48 to 96 hours. more aspiration cycles can be performed in the same time period Originally. 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. o n n y 11 . 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). About 18 hours later the oocytes are observed to determine if fertilization has occurred. medical therapy will not cause sufficient regression to improve fertility rates. • They found that the relative likelihood of pregnancy with the use of clomiphene citrate supraovulation was 2. Follicle aspiration is now being performed routinely through the vagina into the cul-de-sac with sonographic guidance of needle placement. 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. Two main advantages for performing IVF with eggs collected from the dominant follicle in a normal. progestins. unstimulated ovulatory cycle. 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 x • • 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. With the development of sequential culture media it has become possible to allow embryos to develop in vitro to the blastocyst stage. First. Second. 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. nearly all IVF clinics currently utilize some form of ovarian hyperstimulation to increase the number of oocytes obtained at the time of follicle aspiration. on the morning following the day that LH is initially detected in a random urine specimen. the substantial cost of administering gonadotropin and additional days of monitoring that are necessary in stimulated cycles are avoided. GnRH agonists. Use of danazol was associated with the same likelihood of pregnancy as occurred with no treatment. and placement of tubal stents.9 times that of women who re-ceived no treatment. • For women with moderate disease without ovarian endometriomas and minimal adhesions that can be cut at the time of laparoscopy. or 36 hours after intramuscular HCG is given to induce ovulation. and surgical treatment should be undertaken. sperm that has been separated from semen are added to the culture medium. F i l i o e r t z a t i E n d o I V i t r n • • • • • • • 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. prior to transfer into the endometrial cavity. Insemination is best performed on the day prior to spontaneous ovulation.

couples with women in the reproductive age group were infertile—6. and 10% to 15% by abnormalities of sperm transport through the cervical canal. (3) immunologic tests to detect sperm antibodies. embryo culturing. There is no evidence that treatment of an abnormality in the tests just listed significantly improves pregnancy rates compared with withholding therapy. 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.2) chance of • • • . the couple should be informed that the chances for conception are much reduced. 30% to 40% by pelvic disease. and embryo transfer into the uterus are avoided by this technique. The incidence of infertility steadily increases in women after age 30. Of all the causes of infertility. A sustained rise in BBT or a serum progesterone level greater than 5 ng/mL is presumptive evidence of ovulation. including (1) measurement of serum prolactin and TSH in ovulatory women. it is important for the couple to consider psychological counseling. ovarian hyperstimulation and laparoscopy are still required. (2) a late luteal-phase endometrial biopsy. semen analysis. 75% in 6 months. Although IVF. developing a clinical pregnancy in each ovulatory cycle. Among fertile couples who have coitus in the week before ovulation. treatment of anovulation results in the greatest success.f l l f ( • • • • • A modification of IVF. A midluteal-phase serum progesterone level above 10 ng/mL is an indication of adequate luteal function. Other diagnostic tests for infertility. g a m n a r a p a i e t e i t o n t a r n s e r G I F T ) .S. 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. called can be used if the infertile woman has functioning oviducts. A high percentage of fertile men will have at least one abnormal parameter in their semen analysis. and this information should be restated at subsequent visits. and (4) bacterial culture of cervical mucus and semen. and 90% at the end of 1 year. Finally. 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. In women with a normal HSG. a hysteroscopy is unnecessary because it will not detect additional abnormality. and a sustained increase of BBT occurs following ovulation. When the period during which conception should be expected has been exceeded. there is only about a 20% (monthly fecundability of 0. In the United States approximately 10% to 15% of cases of infertility are caused by anovulation. Cryopreservation allows embryos that cannot be immediately transferred to the woman to be stored for future use. The basal body temperature (BBT) increases when circulating levels of progesterone increase. ) u a l 12 . The primary diagnostic tests for infertility are documentation of ovulation. and Modifications of GIFT include With ZIFT the oocytes are fertilized in vitro and transferred 24 hours later. If more than four eggs are fertilized in a given cycle.2 million women. 30% to 40% by an abnormality of semen production. and hysterosalpingogram (HSG). the excess embryos can be frozen if they are of good quality. the couple should be informed that further testing and treatment are not warranted and other alternatives such as adoption should be considered. In about half of fertile couples attempting to conceive the woman will become pregnant in 3 months. When ovulation is induced with clomiphene citrate and no other causes of infertility are present. Infertile couples who conceive do not have higher rates of spontaneous abortion or perinatal mortality than age-matched control subjects. conception rates over time are similar to those • • • • • • • • • • • • • f l l f ( ) b o g n a r a o p a n a r n T F t e i t i t s e r Z I t y z b f ( m o a g a r n T e r s t e t s e r E S y T Final Couseling • If intensive treatment of the infertile couple with various techniques fails to result in conception after 2 years. About 10% to 20% of cases are unexplained. With this technique both oocytes and sperm are placed into the oviduct through a catheter at the time of laparoscopy or minilaparotomy.

If both proximal and distal obstructions of the oviduct exist. Treatment of anovulation with gonadotropin effects an ovulatory rate of about 100%. respectively. About 5% to 10% of women treated with the individualized. and no tubal reconstructive procedures should be attempted. With moderate or severe disease. 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. Discontinuation of therapy is the major reason for the reported difference in ovulation and conception rates in anovulatory women treated with clomiphene. and will not transmit an infectious agent in the semen.of a normal fertile population. nearly all of them being twin gestations. The benefit of second-look laparoscopy after tubal surgery has not been established. IVF is the best therapy. and operative reconstruction should not be performed. The incidences of clinical spontaneous abortion. Semen donors need to be carefully screened to be certain that they are in good health. About 65% of women with mild endometriosis and no other cause of infertility conceive without treatment. Unlike the results of distal tubal reconstruction. The pregnancy rate per cycle with gonadotropins is similar to that following clomiphene therapy (22%). graduated. Proximal tubal obstruction is now usually treated by cannulation of the oviducts with catheters or balloons placed under hysteroscopic visualization. partial ovarian destruction by electrocautery or laser through the laparoscope is effective in inducing ovulation. do not have a potentially inherited disorder. The prognosis for fertility after tubal reconstruction depends on the amount of damage to the oviduct as well as the location of the obstruction. Conception rates for women treated surgically have been reported to be • • • • • • • • • • • • • • • • • • • • • • • • 13 . The pregnancy rate after salpingolysis and fimbrioplasty for partial distal obstruction is about 65%. No medical therapy for endometriosis has proved to increase pregnancy rates compared with no treatment. 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. with a high percentage (about one fourth) being tubal pregnancies. ectopic gestation. IVF may be attempted if the endometrial cavity is not infected. intrauterine fetal death. When conception occurs after clomiphene treatment in anovulatory women. the incidence of multiple gestation is increased to about 8%. Pregnancy rates for oligospermia following intrauterine insemination are in the 25% to 35% range. sequential regimen of clomiphene citrate fail to ovulate with the highest dosage. the use of microsurgery has improved intrauterine pregnancy rates for proximal tubal disease. Women with pelvic tuberculosis should be considered sterile. 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. and congenital malformation are not significantly increased. Formation of ovarian cysts is the major side effect of clomiphene treatment. • Because antibodies to HIV may not develop for several months after infection. pregnancy rates with expectant management are 25% and 0%. Overall conception rates following salpingostomy are in the 30% range. intrauterine pregnancy is uncommon. Pregnancy rates for women with mild endometriosis can be increased with the use of controlled ovarian hyperstimulation and intrauterine insemination but not with danazol. The incidence of spontaneous abortion after HMG therapy is high (25% to 35%).

The optimal treatment for all causes of sperm abnormalities is ICSI. No data conclusively demonstrate that the finding of antisperm antibodies in either member of the couple is a cause of infertility. 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. Luteal-phase deficiency. have patent oviducts. About half of infertile women with myomas conceive after myomectomy. With this technique. After six cycles the cumulative pregnancy rate is about 60%. If an infertile couple fails to conceive after 2 years of therapy. 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. they should be informed the chances for conception are remote. pregnancy rates per cycle are similar to that of IVF performed for other causes of infertility. and whose male partner has at least 5 million motile sperm in the ejaculate. is probably a normal biologic variant and not a true cause of infertility. The rate of pregnancy following IVF is directly related to the number of embryos placed in the uterine cavity. as currently diagnosed histologically. The pregnancy rate per cycle of IVF remains relatively constant for about six cycles after which it declines.in the 50% to 60% range for those with moderate endometriosis and 30% to 40% for those with severe endometriosis. • • • • • • • • • • 14 . There is a high spontaneous abortion rate (about 30%) for pregnancies after IVF.