Dr. Nikolaos Mouchsiadis MD.

After, Uterine cavity!
Not bad?!

Before!
Intrauterine Polyp, size ( 50 ×30 mm)

It was big uterus and wasn't so easy to remove it!
But, as always we did it!

Surgical Management of Ectopic Pregnancy


Overview

Background
The first successful surgical management of a ruptured tubal pregnancy occurred in April 1883, when the British surgeon Robert Lawson Tait performed a laparotomy and ligated the ruptured tube and the broad ligament. At a time when ectopic pregnancy was associated with a greater than 60% mortality rate, Tait lost only 2 of the first 42 patients on whom he operated.
By the 1920s, laparotomy and ligation of the bleeding vessels with removal of the affected tube had become the standard of care, and it remained so until the late 1970s, when operative laparoscopy and salpingostomy replaced laparotomy and salpingectomy.
In the 1980s and 1990s, medical therapy for ectopic pregnancy was implemented; it has now replaced surgical therapy in many cases. Thus, in less than 3 decades, management of ectopic pregnancy has evolved from emergency surgical treatment to conservative medical treatment.[1, 2, 3]
Relevant Anatomy
The uterine tubes are uterine appendages located bilaterally at the superior portion of the uterine cavity. These tubes exit the uterus through an area referred to as the cornua, forming a connection between the endometrial and peritoneal cavities. Each uterine tube is approximately 10 cm in length and 1 cm in diameter and is situated within the mesosalpinx. The mesosalpinx is a fold in the broad ligament. The distal portion of the uterine tube ends in an orientation encircling the o***y. The primary function of the uterine tubes is to transport s***m toward the egg, which is released by the o***y, and to then allow passage of the fertilized egg back to the uterus for implantation.
Indications
Indications for surgical treatment of ectopic pregnancy include the following:
• The patient is not a suitable candidate for medical therapy.
• Medical therapy has failed.
• The patient has a heterotopic pregnancy with a viable intrauterine pregnancy.
• The patient is hemodynamically unstable and needs immediate treatment.

Contraindications
The only contraindications to surgical management are the following:
• The patient has a medically treatable ectopic pregnancy.
• The patient has other medical conditions that would make the risks associated with surgery unacceptable.

Preparation

Preoperative Evaluation
Optimal surgical management of an ectopic pregnancy depends on several factors, including the following:
• The patient’s age, history, and desire for future fertility
• History of previous ectopic pregnancy or pelvic inflammatory disease (PID)
• The condition of the ipsilateral tube (ie, ruptured or unruptured)
• The condition of the contralateral tube (eg, adhesions, tubal occlusion)
• The location of the pregnancy (eg, interstitium, ampulla, isthmus)
• The size of the pregnancy
• The presence of confounding complications
In a patient who has completed childbearing and no longer desires fertility, in a patient with a history of an ectopic pregnancy in the same tube, or in a patient with severely damaged tubes, total salpingectomy is the procedure of choice. The presence of uncontrolled bleeding and hemodynamic instability warrants the choice of radical surgery over conservative methods. The preferred approach varies according to the location of the pregnancy.
In all instances, regardless of desired fertility, fully inform the patient of the possibility of a laparotomy with bilateral salpingectomy.

Initial Preoperative Measures
Obtain large-bore venous access and start fluid resuscitation. Make sure blood is available. Do not delay the operation; the patient has an active bleeding site, and it must be stopped as soon as possible. Place a Foley catheter before starting the procedure.
Insertion of either a Hulka tenaculum or a Harris-Kronner uterine manipulator/injector (HUMI) device into the uterus may facilitate manipulation of the tube during surgery.

Technique

Overview
With advances in the ability to make the diagnosis earlier and improvements in microsurgical techniques, conservative surgery has replaced the once-standard laparotomy with salpingectomy. Within the past 2 decades, a more conservative surgical approach to unruptured ectopic pregnancy using minimally invasive surgery has been advocated to preserve tubal function.
The conservative approaches include linea
Surgical therapy may be provided either via open laparotomy or via the laparoscopic route. Laparoscopy has become the recommended approach in most cases. Laparotomy is usually reserved for patients who are hemodynamically unstable or patients with cornual ectopic pregnancies. It is also preferred for surgeons inexperienced in laparoscopy and for patients in whom a laparoscopic approach is difficult (eg, secondary to the presence of multiple dense adhesions, obesity, or massive hemoperitoneum).
Multiple studies have demonstrated that laparoscopic treatment of ectopic pregnancy results in fewer postoperative adhesions than laparotomy. Furthermore, laparoscopy is associated with significantly less blood loss and a reduced need for analgesia. Finally, laparoscopy reduces cost, hospitalization, and convalescence period.
Risk factors for converting laparoscopy to laparotomy should be considered; these include multiple prior surgeries, pelvic adhesions, skill of the surgeon and surgical staff, availability of the equipment, and condition of the patient.
A meta-analysis of medical versus surgical therapy for ectopic pregnancy indicated that laparoscopic surgery for ectopic pregnancy was the most cost-effective approach.[4, 5] Medical therapy using methotrexate was also cost-effective for beta human chorionic gonadotropin (β-hCG) levels lower than 3000 mIU/mL. Both approaches were found effective in appropriately selected patients with adequate follow-up.
Regardless of the route of approach, salpingectomy is indicated in the following situations:
• The ectopic pregnancy has ruptured.
• Future fertility is not desired.
• The ectopic pregnancy represents a failure of sterilization.
• The tube has previously been reconstructed.
• Sterilization is requested.
• Hemorrhage continues after salpingotomy.
• The ectopic pregnancy is in the blind-ending distal segment after a previous partial salpingectomy.
• The current pregnancy represents a chronic tubal pregnancy.
In the absence of any of the above indications for salpingectomy, salpingotomy may be performed.
If the ectopic pregnancy is at the fimbria, then fimbrial evacuation is feasible, in the absence of indications for salpingectomy.
Partial salpingectomy may be indicated if the pregnancy is in the midportion of the tube, if none of the indications for salpingectomy is present, and if the patient may be a candidate for later tubal reanastomosis.
General Recommendations

Throughout the procedure, take care to minimize blood loss and reduce the potential for retained trophoblastic tissue, which can reimplant and persist. Remove large gestations in an endoscopic bag, and perform copious irrigation and suctioning to remove any remaining fragments. Inspect the peritoneal cavity and remove any detected residual trophoblastic tissue.
Note the condition of the contralateral tube, the presence of adhesions, or other pathologic processes because this helps in the postoperative counseling of the patient with regard to future fertility potential.
Linear Salpingotomy/Salpingostomy

Linear salpingostomy along the antimesenteric border to remove the products of conception is the procedure of choice for unruptured ectopic pregnancies in the ampullary portion of the tube. Ectopic pregnancies in the ampulla are usually located between the lumen and the serosa and, thus, are ideal candidates for linear salpingostomy. Several studies have not found primary closure of the tubal incision (salpingotomy) to have any significant advantages over healing by secondary intention (salpingostomy).
Open technique
The involved tube is identified and freed from surrounding structures. To minimize bleeding, a dilute solution containing 20 U of vasopressin in 20 mL of isotonic sodium chloride solution (some authors use 50 mL) may be injected into the mesosalpinx just below the ectopic pregnancy. Make sure that the needle is not in a blood vessel by aspirating before injecting. Intravascular injection of vasopressin may precipitate acute arterial hypertension and bradycardia and is contraindicated in patients with ischemic heart disease.
Next, using a microelectrode, scissors, knife, harmonic scalpel, or laser, make a 1- to 2-cm linear incision on the antimesenteric side of the tube along the thinnest segment of the gestation (see the following images).
Salpingectomy technique. Pedicle is cut free and ligated with suture ligature. Salpingotomy technique. 1- to 2-cm incision is made on antimesenteric side of tube with needle electrode. Salpingotomy technique. 1- to 2-cm incision is made on antimesenteric side of tube with knife. Salpingotomy technique. Linear incision is made on antimesenteric side of ampullary portion of fallopian tube.
At this time, the pregnancy usually protrudes out of the incision and may slip out of the tube (see the image below).
Laparoscopic picture of ampullary ectopic pregnancy protruding after linear salpingostomy was performed.
Occasionally, the ectopic pregnancy must be teased out with forceps (see the image below).
Ectopic pregnancy. Schematic of tubal gestation being teased out after linear salpingostomy.
Alternatively, aquadissection, which uses pressurized irrigation to help dislodge the pregnancy, may be employed. Insert the aquadissector, or a syringe filled with saline, deep into the incision. The pressurized fluid from the aquadissector (or syringe) dissects and dislodges the ectopic pregnancy and clots.
Irrigate the bed well. If trophoblastic tissue remains, the prior injection of vasopressin may lead to anoxia and death of the trophoblasts, preventing postoperative growth. Further dissection may damage the tube and is not usually performed.
Some ampullary pregnancies can be teased out and expressed through the fimbrial end (milking of the tube) by using digital expression, suction, or aquadissection. However, this approach carries with it a higher rate of bleeding, persistent trophoblastic tissue, tubal damage, and recurrent ectopic pregnancy (33%).
Bleeding may be controlled by applying pressure with blunt tissue forceps for 5 minutes. Arterial bleeding may require pinpoint bipolar desiccation. Diffuse venous bleeding is best controlled with monopolar current. A spark or arc is created by using a current of 25-50 W through an electrode in noncontact mode.
Uncontrollable bleeding may require application of a suture ligature to provide compression for 10 minutes. The ligature is then released. If bleeding continues, suture of the mesosalpingeal vessels may be attempted.
The tubal incision is left open and not repaired.

Laparoscopic technique

Infiltrate the mesosalpinx with vasopressin (20 IU in 50 mL of isotonic sodium chloride solution [ie, normal saline or NS]; some authors use only 10 IU in 50 mL of NS). Avoid intravascular injection because it is contraindicated in patients with ischemic heart disease. It frequently causes hypertension.
With the knife or needle electrode, make a 1- to 2-cm incision on the antimesenteric side of the tube. Insert the aquadissector deep into the incision. Fluid from the aquadissector, under pressure, dissects and dislodges the ectopic pregnancy and clots.
Irrigate the bed well. If trophoblastic tissue remains, the use of vasopressin may lead to anoxia and death of the trophoblasts, preventing postoperative growth. Further dissection may damage the tube and is not usually performed.
The products of conception are then removed through the 12-mm sleeve. If necessary, products of conception can be reduced to smaller pieces with biopsy forceps or the aquadissector.
Bleeding may be controlled by applying pressure with grasping forceps for 5 minutes. Arterial bleeding may require pinpoint bipolar desiccation. Diffuse venous bleeding is best controlled with monopolar current. A spark or arc is created by using a current of 25-50 W through an electrode in noncontact mode.
Uncontrollable bleeding may require the application of an endoscopic loop to provide compression for 10 minutes. The ligature is then released. If bleeding continues, suture of the mesosalpingeal vessels may be attempted.

Total Salpingectomy

In some cases, salpingectomy, either total or partial (see Partial Salpingectomy) is preferable to salpingostomy. This is true for isthmic pregnancies, where the endosalpinx is usually damaged. Patients with such pregnancies do poorly with linear salpingostomy and have a high rate of recurrent ectopic pregnancy.
Total salpingectomy can be achieved by progressively coagulating and cutting the mesosalpinx, starting from the fimbriated end and advancing toward the proximal isthmic portion of the tube. At this point, the tube is separated from the uterus by coagulating and excising with scissors or laser.

Open technique

Clamp the tube between the uterus and the ectopic pregnancy using a Pean or similar clamp. Cut the pedicle free and ligate the pedicle with a suture ligature (see the following image).
Salpingectomy technique. Pedicle is cut free and ligated with suture ligature.
Clamp, cut, and ligate the tuboovarian artery, while preserving the uteroovarian artery and ligament. Continue to clamp, cut, and ligate the mesosalpinx until the tube is free and can be removed.

Laparoscopic technique

Desiccate the tube between the uterus and the ectopic pregnancy using bipolar cautery. Compress and desiccate the tuboovarian artery while preserving the uteroovarian artery and ligament. Cut along the desiccated path, closer to the specimen, leaving a pedicle for hemostasis. Repeat until the tube is free and can be removed.

Partial Salpingectomy
Segmental tubal resection is performed by grasping the tube at the proximal and distal borders of the segment of the tube containing the gestation and coagulating thoroughly from the antimesenteric border to the mesosalpinx. This portion of the tube is then excised. The underlying mesosalpinx is also coagulated and excised, with particular attention paid to minimizing the damage to the surrounding vasculature.
Delayed microsurgical reanastomosis can be performed to reestablish tubal patency if enough healthy fallopian tube is present. Take care to minimize the thermal injury to the tube during excision, so that an adequate portion of healthy tube remains for the reanastomosis.

Open technique
Place a clamp through an avascular area in the mesosalpinx under the ectopic pregnancy. This creates a space through which 2 free ties are placed. Tie the free ties around the tube on each side of the ectopic pregnancy. Cut free and remove the isolated portion of the tube containing the ectopic pregnancy.

Laparoscopic technique
Perform bipolar desiccation across the tube on both sides of the ectopic pregnancy. Divide the tube at the sites of desiccation. The mesosalpinx under the ectopic pregnancy can then be either desiccated or ligated with an endoscopic loop. Remove the products of conception.

Fimbrial Evacuation
Open technique
Grasp the fimbria and insert the aquadissector or a syringe filled with saline. Fluid under pressure dissects and dislodges the ectopic pregnancy and clots. Remove the products of conception.
Laparoscopic technique
Grasp the fimbria and rotate it to allow insertion of the aquadissector. Fluid under pressure dissects and dislodges the ectopic pregnancy and clots. Remove the products of conception.

Post-Procedure

Postoperative Care
Proper pain control and hemodynamic stability are important postoperative considerations. Most often, patients treated with laparoscopy are discharged on the same day of surgery; however, overnight admission may be necessary for some patients to monitor postoperative bleeding and achieve adequate pain control. Patients treated by laparotomy are usually hospitalized for a few days.
Patients who were in shock or had to receive blood transfusions generally require a longer postoperative observation period, which should include observation that the kidneys are functioning normally and the patient has regained normal hemodynamics.
Expected Outcomes
The prognosis for patients with an ectopic pregnancy is good for those with an early diagnosis. Conservation of fertility is frequently achievable. The earlier the diagnosis is made and treatment administered, the higher the likelihood of subsequent fertility.
Thirty years ago, when the diagnosis was seldom made before rupture, the likelihood of a subsequent healthy term pregnancy was only approximately 35%. Currently, that number is closer to 85%. The difference is in the earlier diagnosis and treatment before the ectopic pregnancy can grow large enough to severely damage the tube.
Another factor in the improved fertility rate may be related to the decrease in salpingectomies and the increase in salpingostomies. In a retrospective cohort study of 651 women who underwent an operation for their first ectopic pregnancy, Bangsgaard et al reported a fertility rate of 88% after conservative surgery (salpingostomy) versus only 66% after radical surgery (salpingectomy).[6] They also found no difference in recurrence rates for ectopic pregnancy in the 2 groups.
However, 8% of the group that underwent conservative treatment had persistent ectopic pregnancies. These were all treated with either methotrexate or repeat surgery. This shows the need to monitor all conservatively treated patients with serial beta human chorionic gonadotropin (β-hCG) measurements until values return to negative.
Complications
Cervical pregnancy is not exactly a complication but should be discussed nonetheless. A cervical pregnancy is an ectopic pregnancy that has implanted in the cervix. It can cause severe hemorrhage if it starts to separate from the cervix. Few muscle fibers are in the cervix; thus, no constriction occurs around the hypertrophied blood vessels that developed for the pregnancy. With no pressure on the vessels, profuse hemorrhage can occur.
In recent years, ultrasonographic imaging has improved to the point where the diagnosis of cervical pregnancy is made much more frequently in asymptomatic patients. The improvement in diagnosis has made many more management options available.
Previously, the only option was surgical treatment, with curettage of the implantation site. This often led to such profuse hemorrhage that surgeons recommended opening the patient’s abdomen and placing ligatures around the uterine arteries or hypogastric arteries before starting the curettage. Hysterectomy was frequently the result.
Currently, the recommended treatment is either hysterectomy for those who do not desire fertility or methotrexate for those who do. Because patients who receive methotrexate occasionally develop severe hemorrhage, they should be observed closely for 1-2 weeks after therapy. An interventional radiologist should be available for arterial embolization if severe hemorrhage occurs as the pregnancy separates from the cervix.
Long-Term Monitoring
After surgical excision of the ectopic gestation, weekly monitoring of quantitative β-hCG levels is necessary until the level is zero to ensure that treatment is complete. This is especially true after treatment with conservative surgery (ie, salpingostomy), which carries a 5-15% rate of persistent trophoblastic tissue. The average time for β-hCG to clear the system is 2-3 weeks, but up to 6 weeks can be required.
After tube-sparing surgical removal of an ectopic pregnancy, a fall in β-hCG levels of less than 20% every 72 hours represents incomplete treatment. Although most of these cases are caused by incomplete removal of trophoblastic tissue, some actually may represent multiple ectopic pregnancies in which only 1 gestation is initially recognized and treated.
The incidence of persistent trophoblastic tissue is greater with higher initial β-hCG levels and is relatively rare with titers less than 3000 IU/L. The risk of persistent trophoblastic tissue is very significant with a hematosalpinx greater than 6 cm in diameter, a β-hCG titer greater than 20,000 IU/L, and a hemoperitoneum greater than 2 L.
Whereas resolution without any further intervention is the general rule, the persistence of trophoblastic tissue has been associated with tubal rupture and hemorrhage even in the presence of declining β-hCG levels. Further medical treatment with methotrexate or surgery in symptomatic patients may be necessary if β-hCG levels do not decline. Some authors have suggested administration of a prophylactic dose of methotrexate after conservative surgery to reduce the risk of persistent ectopic pregnancy.
Patients should all be on some form of effective contraception until their β-hCG levels have returned to nonpregnant levels.

Infertility Treatment
A consultation once the evaluation has been completed is imperative. A treatment plan should be generated according to the diagnosis, duration of infertility, and the woman's age. If pregnancy has not been established within a reasonable time, further evaluation and/or an alternative treatment plan should be considered.

Treatment of Cervical Factors
Chronic cervicitis may be treated with antibiotics. Reduced secretion of cervical mucus due to destruction of the endocervical glands by previous cervical conization, freezing, or laser vaporization responds poorly to low-dose estrogen therapy. The easiest and most successful treatment is intrauterine insemination (IUI).[103] Similar treatments apply when oligos***mia, hypos***mia, and ejaculatory disorders such as impotence, hypospadias, or retrograde ej*******on are present.[104, 105, 106] Patients with azoos***mia that is not amenable to in vitro fertilization/intracytoplasmic s***m injection treatment benefit from artificial insemination (AI) with donor s***m.[107]

Artificial insemination can be performed by depositing the s***m at the cervical level (cervical insemination)[105] or inside the endometrial cavity (intrauterine insemination). Cervical insemination has almost been abandoned because of its low success and has been relegated only to cases in which the s***m count is normal, such as in artificial insemination using donor s***m or if the sample has elevated white cells.

For intrauterine insemination, in vitro fertilization, and intracytoplasmic s***m injection procedures, the removal of certain components of the ej*****te (ie, seminal fluid, excess cellular debris, leukocytes, morphologically abnormal s***m) with the retention of the motile fraction of s***m is desirable.

For most specimens, the greatest recovery of the motile portion results from separation via centrifugal filtration through a discontinuous density gradient system. However, for certain very poor specimens with low original concentrations of motile s***m, the use of the gradient system results in such a negligible recovery as to render it useless. The recourse for these specimens is to remove the seminal fluid by successive media washes.

A small number of specimens have acceptable original concentrations of motile s***m but poor recoveries with the gradient system. These specimens benefit most from layering a washed pellet of s***m with nutrient media and allowing the motile fraction to swim up into the media before being separated.[108]

After s***m preparation, the s***matozoa are enhanced in motility and become activated and ready to fertilize an oocyte. Intrauterine insemination is performed during a natural cycle or after ovulation induction with CC or gonadotropins. The procedure is performed 30-34 hours after the spontaneous LH surge or 36 hours after the administration of 10,000 U of hCG.[109] The s***m is delivered into the endometrial cavity using an intrauterine insemination catheter. After injection of the s***m, the patient remains in the recumbent position for 10-15 minutes.

The average pregnancy rate achieved after a natural-cycle intrauterine insemination is 8%. The rate increases to 10-12% after CC ovulation induction and to 12-15% per cycle after hMG/hCG ovulation induction. Of the successful pregnancies, 85% are achieved within the first 4 cycles of intrauterine inseminations.

Homologous insemination refers to the use of s***m from the patient's partner. Heterologous or therapeutic insemination, formerly called artificial insemination by donor s***m, refers to the use of frozen s***m that has been quarantined for at least 6 months.[107] Thereafter, the specimen is ready to use once the donor has undergone the necessary screening tests required by the tissue bank, the US Food and Drug Administration (FDA), and the American Society for Reproductive Medicine (ASRM).[110] The source of the s***m can be either anonymous or from a donor designated by the couple. A cumulative pregnancy rate of 80% is achieved during the first 6 cycles of therapeutic insemination.

Treatment of Uterine Factors
Until in vitro fertilization became available, a patient with congenital absence of the uterus and va**na (Rokitansky-Küster-Hauser syndrome) had no chance to have a biologic child. Today, it is feasible by using a surrogate mother or gestational carrier. Once patients desire to have children, they proceed with stimulation of the ovaries, oocyte aspiration, and in vitro fertilization, but the embryos are transferred to a gestational carrier (see In Vitro Fertilization).

The treatment of uterine malformations depends on the severity of the problem. Fertility is not an issue for some patients affected by DES, and they remain undiagnosed until they have an abnormal Papanicolaou test result. Those who do have fertility problems are treated according to the following guidelines:[111, 112, 113]

Chronic cervical factor of absence of mucus - Intrauterine insemination
Cervical incompetence - Cerclage
Damage/absence of fallopian tubes (ectopic) - In vitro fertilization
Unicornuate uterus
A unicornuate uterus remains undetected unless fertility is compromised. Patients with this type of uterus can have a normal term pregnancy. Most problems are related to premature labor and pregnancy loss. Unicornuate uterus is associated with renal abnormalities including absence of a kidney or presence of a pelvic kidney; this occurs in 15% of cases. Thus, an intravenous pyelogram must be performed once this diagnosis is made. Whether interventions before conception or early in pregnancy, such as resection of the rudimentary horn and prophylactic cervical cerclage, decidedly improve obstetrical outcomes is uncertain; however, current practice suggests that such interventions may be helpful. Women presenting with a history of this anomaly should be considered high-risk obstetrical patients.[114]

Bicornuate uterus
A bicornuate uterus causes only minimal problems with infertility (if any). A bicornuate uterus can be associated with a history of recurrent miscarriages, and its repair is indicated only if other etiologies for the miscarriage have been excluded (see Surgical intervention below).

Arcuate uterus
In general, an arcuate uterus does not cause infertility. Whether it should be corrected in cases of primary infertility is controversial.

Septate uterus
The hypothesis that a uterine septum can cause infertility is controversial. Advising surgery in cases of primary infertility is difficult. The avascular nature of the septum is theorized to interfere with implantation and maintenance of the embryo.

Surgical Intervention
Uterine anomalies can be corrected through operative hysteroscopy under general anesthesia or conscious sedation.[115] Ideally, the procedure should be performed during the early follicular phase and under laparoscopic surveillance to decrease the risk of uterine perforation. Furthermore, laparoscopy assists in the differential diagnosis between a septate and a bicornuate uterus. A bicornuate uterus is characterized by the presence of an indentation at the fundus.

The 2 techniques are the Strassman metroplasty and the Jones metroplasty. The Strassman metroplasty consists of performing an incision at the fundus of the uterus between both cornual areas and closing the defect with an anteroposterior suture. The Jones metroplasty consists of resecting the septum using an anteroposterior wedge incision and closing the defect in the same direction (see the images below).[116, 117, 118]

Infertility. Metroplasty - Strassman technique. Image courtesy of Clifford R. Wheeless, Jr, MD.

Infertility. Metroplasty - Jones technique. Image courtesy of Clifford R. Wheeless, Jr, MD.
Uterine synechiae
Uterine synechiae are corrected using operative hysteroscopy. The surgery is performed during the early follicular phase. Once the synechiae have been resected, leaving an intrauterine balloon for 7 days is advisable to prevent a recurrence of adhesions. The patient should receive prophylactic antibiotics and uterine relaxants (eg, ibuprofen) during these 7 days to prevent infection and balloon expulsion, respectively. The patient should be prescribed high-dose estradiol (5 mg qd for 21 d) followed by medroxyprogesterone (10 mg for 10 d). A postoperative HSG should be performed 2 months later. In many instances, more than one hysteroscopy is required for total resection.

Endometrial polyps
Endometrial polyps are removed through operative hysteroscopy associated with a dilatation and curettage, if necessary. An HSG follow-up procedure is not necessary. To prevent further polyp development associated with anovulation, the patient should have withdrawal bleeding at least every 6 weeks.

Myoma treatment
In general, small and asymptomatic myomas do not require treatment, but the patient should be periodically monitored. Fibroids should be treated if they are associated with abnormal uterine bleeding or if they are thought to be the cause of infertility. Three modalities are used to treat myomas: medical treatment, surgical treatment, and embolization.

Medical treatment is a temporary treatment, ideally used for patients who are close to menopause or who are risky surgical candidates. However, medical treatment can be used to reduce the myoma size prior to removal. GnRH analog ([GnRHa], leuprolide acetate, nafarelin acetate, goserelin acetate) causes down-regulation of the pituitary, inducing chemical menopause after injections of 3.75 mg intramuscularly every 4 weeks for a period of up to 6 months.[119, 120, 121, 116] Disadvantages of this treatment include symptoms of menopause, osteoporosis, and recurrence of the myomas after discontinuation of the treatment.
Surgical treatment of myomas is indicated in cases of abnormal uterine bleeding, when the myoma is implicated in recurrent miscarriages or when it is thought to interfere with embryo implantation. The 3 classes of surgical techniques are conventional laparotomy, operative laparoscopy, and operative hysteroscopy.
Laparotomy: This technique is indicated for large myomas, for submucous myomas larger than 3 cm in diameter, or for myomas that, regardless of being submucous, have a portion of the myoma that compromises the myometrium so that a complete resection through the hysteroscopy is not feasible.
Operative laparoscopy: This technique is indicated for pedunculated and superficial intramural myomas. This technique should be reserved for myomas with a diameter less than 6 cm.[122] Several cases have been reported of uterine rupture during pregnancy because the reconstruction of the uterus after laparoscopic myomectomy was not as good as a myomectomy performed using laparotomy.[123]
Operative hysteroscopy: The removal of a submucous fibroid using hysteroscopy should be limited to small fibroids (≤3 cm) with minimal compromise of the myometrium.[76] This is important to decrease the risk of excessive bleeding and to decrease the risk of electrolyte imbalance, water intoxication, and pulmonary edema from excessive intravasation of Hyskon, glycine, or sorbitol used during the procedure. To avoid this complication, the circulating nurse must record the amount of distention fluid injected and the amount recovered in the suction device. If a deficit of greater than 1 L is recorded, the procedure should be terminated, and, preferably, the myomectomy should be completed in a second hysteroscopic attempt. The patient's electrolyte levels must be checked to consider the need for diuretics. Uterine synechiae development is a potential complication after the surgery; therefore, a postoperative HSG should be part of follow-up care.
Uterine fibroid embolization (UFE) consists of catheterization of the uterine artery and the injection of microbeads of polyvinyl alcohol to selectively occlude the circulation of the fibroid. The procedure is performed by interventional radiology and requires overnight admission for the patient.[124] It is NOT intended for patients who desire fertility.
Treatment of Tubal and Peritoneal Factors
The treatment of tubal-factor infertility underwent major changes, especially during the last quarter of the century when microsurgery became available.[125, 126] Tubal reconstruction was the only hope for those patients before assisted reproductive therapy became available.

Because of the intimate relationship between the fallopian tubes and the other pelvic organs and because, in the great majority of the cases, peritoneal pathology involves tubal pathology, the treatments of these factors are discussed together.

Tubal and peritoneal factor infertility treatment requires a good surgeon who is skilled in currently available techniques.[127] The patient's age and the severity of the tubal pathology play important roles in the selection of patients, as do any other infertility issues such as the presence of endometriosis and severe pelvic adhesions. Before surgery, the HSG films and results of previous laparoscopies should be thoroughly reviewed to decide on the type of surgical technique that is required and to explain to the patient the expected degree of success and risks involved with the procedure.

Tubal obstruction and lysis of adhesions can be corrected through laparotomy, operative laparoscopy, and, in special circumstances, through operative hysteroscopy and tubal cannulation.

Laparotomy is indicated in patients with severe pelvic adhesions that compromise the bowel, ovaries, and tubes, with obliteration of the cul-de-sac.[128] The aim of the procedure is to correct what is necessary to allow the normal transport of the gametes; complete restoration of the anatomy is not intended.[129] Lysis of adhesions should be meticulous, using hydrodissection and fine instruments. Blunt dissection should be avoided. Constant irrigation with Ringer lactate solution and heparin prevents fibrin formation. Meticulous hemostasis is imperative.[130, 131, 132]

Operative laparoscopy was reintroduced into the surgical armamentarium in the 1950s; however, in the 1970s, Semm developed different procedures and operative instruments that currently allow for the outpatient laparoscopic surgical treatment of multiple tuboperitoneal pathologies,[86] electrocautery, endocoagulation, lasers, and ultrasonography scalpels facilitate the performance of operations that otherwise used to require a laparotomy.

Operative hysteroscopy associated with tubal cannulation is helpful to treat cornual obstruction.

Fimbrial phimosis and periadnexal disease can be treated with laparoscopy.[133, 134, 135, 136, 137] The pregnancy rate after salpingolysis is 50-60% during the first year after treatment. Fimbrioplasty for fimbria agglutination or phimosis without destruction of the cilial epithelium is equally successful. The incidence rate of ectopic pregnancy after surgery is in the range of 5%.

Treatment of hydrosalpinx (distal tubal obstruction) with salpingostomy can be performed through microsurgery or operative laparoscopy. No difference in the pregnancy rate occurs if a skillful microsurgeon or laparoscopist performs the salpingostomy. The success of the procedure is related to the diameter of the hydrosalpinx and to the damage to the cilial epithelium. If the cilial epithelium has been destroyed, the outcome of the procedure is poor, and it is better to perform a salpingectomy in preparation for future IVF. The pregnancy rate fluctuates from 20-35%, and the expected ectopic pregnancy rate is as high as 20%.

Before treating cornual obstruction, the diagnosis should be confirmed. In many cases, cornual obstruction diagnosed on HSG represents simple cornual spasm. Before performing a tubocornual anastomosis, the patient should have a diagnostic laparoscopy associated with tubal cannulation by hysteroscopy.[138, 139, 140] If one tube remains open, anastomosis is not needed because pregnancy can be achieved in 50% of cases. The success rate of tubocornual anastomosis ranges from 20-58%. The ectopic pregnancy rate is 5-7%. If the obstruction is caused by salpingitis isthmica nodosa or fibrosis, the best results are achieved through IVF.[141]

Surgical preparation for IVF
While the surgeon should be as conservative as possible, he or she should consider that the patient is better served with a single well-functioning fallopian tube than with 2 defective tubes, which elicits an increased risk for ectopic pregnancy or recurrence of pelvic adhesions. If the fallopian tubes are beyond repair, bilateral salpingectomy with destruction of the cornual area is recommended in preparation for IVF.

Tubal obstruction due to elective sterilization is better repaired with microsurgery, although the modern tendency is to perform the anastomosis using operative laparoscopy.[142, 26, 143] In either event, knowing in advance what type of tubal ligation technique was used is important. Unfortunately, tubal cauterization destroys a large amount of tissue, so the amount of fallopian tube remaining is often not long enough to facilitate a successful reanastomosis.

Before anastomosis, evaluate the patient using HSG and laparoscopy findings to measure how far proximal and distal fragments of the fallopian tubes remain from the tubal ligation. To have a successful reanastomosis, the final tube should measure at least 4.5 cm. If fimbriectomy was performed, no treatment is available other than IVF. The best candidates for tubal reanastomosis are patients who had tubal ligation by the method of fallopian ring, Filshie clip, or Pomeroy.[143] The pregnancy rate following a tubal reanastomosis performed by a skilled surgeon fluctuates from 70-80%. The ectopic pregnancy rate is approximately 7%.

Treatment of Endometriosis
Endometriosis treatment may be divided according to the severity of the disease and patient needs. Four alternatives are currently available to treat endometriosis: expectant therapy, surgical intervention, medical treatment, and combined therapy.

Expectant therapy
Expectant therapy should be based on a complete workup with diagnosis of very early stages of the disease (minimal) in patients without clinical symptoms, ie, an incidental finding.[144]
A second-look laparoscopy is required for follow-up observation within 6-18 months.
Surgical treatment
Surgical treatment should be directed at destroying the disease using electrocoagulation, laser vaporization, endocoagulation, or excision.[79] Removal of endometriomas and lysis of adhesions complete the treatment.
Most surgical treatment for endometriosis is currently performed through operative laparoscopy.[145, 146, 144] Laparotomy has been relegated to the treatment of severe disease or if a need for hysterectomy arises.[144]
Medical treatment
Medical treatment is directed toward suppressing estrogen production by the o***y. Different modalities of treatment are available. Depending on the therapeutic agent and the duration of treatment, endometriosis can be treated with oral contraceptives, progestins, androgens, or GnRH agonists.
The progestins that can be used and the doses are as follows:
Medroxyprogesterone acetate (eg, Provera 40-60 mg PO qd, Depo-Provera 200 mg IM q2wk)
Megestrol acetate (eg, Megace 20-40 mg PO qd)
Norethindrone acetate (eg, Aygestin 15 mg PO qd)[147, 145, 148, 146, 149, 144]
The androgens used are 17-ethinyl testosterone derivatives (eg, Danazol 400-800 mg PO qd)[150, 151, 152]
The GnRH agonists used are as follows:
Leuprolide acetate (eg, Lupron 3.75 mg IM q4wk or 11.25 mg IM q3mo)
Nafarelin acetate (eg, Synarel 400 mcg IN qd)
Goserelin acetate (eg, Zoladex 3.6 mg SC q4wk or 10.8 mg SC q3mo)
GnRHa therapy can be administered along with cyclic or continuous progestins or with cyclic or continuous estrogen and progestins in cases of severe hot flashes.[151, 144]
Combined therapy
Medical and surgical treatments are usually combined for the treatment of severe endometriosis. No consensus exists as to whether the medical treatment should precede surgery or vice versa.[153, 154, 155] Those who prefer medical treatment first argue that the size of the endometriosis decreases; therefore, surgery will be easier and shorter. Those who prefer surgery first argue that because the size of endometriosis decreases, lesions that cannot be observed during surgery may be present; therefore, the operation is less than ideal and is associated with an increased chance for early recurrence.
Regardless of the treatment approach, establish a 6- to 12-month interval during which a spontaneous pregnancy is expected to occur.
For patients wishing to conceive, the medical approach is not indicated, as it delays treatment for infertility. Medical treatment for minimal to mild disease has not been shown to be of benefit. However, for women with moderate to severe endometriosis, surgical treatment then assisted reproductive therapy can be offered.
A more proactive approach now exists. Ovulation induction and intrauterine insemination are used after completion of the treatment in hopes of expediting the establishment of a pregnancy before relapse of the disease.[156, 157, 32]
Treatment of Ovarian Factors
Ovulation induction is the appropriate treatment for infertile patients who have dysfunction of the hypothalamic-pituitary-ovarian axis. The ovulation induction agents used include clomiphene citrate, hMG, hCG, recombinant FSH, and recombinant LH.

Clomiphene citrate (Clomid, Serophene)
The chemical formula for CC is 2-[p -(2-chloro-1,2-difhenylvinyl) phenoxy] triethylamine dihydrogen citrate. CC is a nonsteroidal estrogen capable of interacting with estrogen receptor–binding proteins in a manner similar to estrogen but in a more prolonged way.[158, 159] Therefore, CC behaves similar to an antiestrogen.

CC has been in clinical use since the early 1960s. Its mechanism of action is still not well understood, but it competes for the estrogen receptor at the hypothalamus, pituitary, and ovarian levels. Because of the action at the estrogen-receptor level within the hypothalamus, CC alleviates the negative feedback effect exerted by endogenous estrogens.[160, 161, 162] As a result, CC normalizes the GnRH release; therefore, the secretion of FSH and LH is capable of normalized follicular recruitment, selection, and development to reestablish the normal process of ovulation.[160, 163]

The standard dose of CC is 50 mg PO qd for 5 days, starting on the menstrual cycle day 3-5 or after progestin-induced bleeding. As an antiestrogen, CC requires that the patient have some circulating estrogen levels; otherwise, the patient will not respond to the treatment. The CC response is monitored using pelvic ultrasonography starting on menstrual cycle day 12. The follicle should develop to a diameter of 23-24 mm before a spontaneous LH surge occurs.

Basal body temperature (BBT) can be used to observe the thermogenic shift (temperature rises 0.5°F above the basal level) induced by the early secretion of progesterone. The only disadvantage with BBT is that in many instances, the shift does not occur in a clear way, and the patient misses the time of ovulation. While BBT is an inexpensive way to monitor ovulation, it is often impractical.

Urinary monitoring of the LH surge (eg, with an LH Predictor Kit) can be a substitute for BBT. The patient should start monitoring the urinary LH secretion daily starting on menstrual cycle day 12. Ovulation usually occurs within the 32-40 hours after the indicative color change. Serum LH determination is more precise, especially when performed in combination with pelvic ultrasonography.

Because of the antiestrogenic effect, CC may thicken the cervical mucus, creating an iatrogenic cervical factor that can be responsible for the lack of pregnancy in a patient who has otherwise ovulated.[164] Other adverse effects associated with CC are hot flashes, scotomas, dryness of the va**na, headache, and ovarian hyperstimulation, which, although rare, has been reported in patients who are sensitive to CC.[165, 166] Whether the use of CC increases the risk of ovarian cancer is unknown, although 2 articles illustrate a potential risk.[167] Other authorities disagree with this assumption.

The principal indications for CC use are oligomenorrhea, especially polycystic ovarian syndrome (PCOS), and for patients with slight menstrual irregularities. Its use has been extended to assisted reproduction technologies.

The use of CC is contraindicated in cases of ovarian cyst, pregnancy, and liver disease. Its use is controversial in patients with a history of breast cancer.

Aromatase inhibitors
Aromatase inhibitors (letrozole, anastrozole) inhibit the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As a result, estrogen levels are dramatically reduced, releasing the hypothalamic-pituitary axis from its negative feedback. Aromatase inhibitors are available for clinical use and FDA approved for treatment of postmenopausal breast cancer, but not for ovulation induction.

When used in the early follicular phase, letrozole inhibits estrogen synthesis, thereby causing enhanced GnRH pulsatility and consequent FSH and inhibin stimulation. This results in normal or enhanced follicular recruitment without the risk of multiple ovulation and ovarian hyperstimulation syndrome. Letrozole has a very short half-life (45 hours) and, therefore, is quickly cleared from the body. For this reason, it is less likely to adversely affect the endometrium and cervical mucus. In a recent meta-analysis, letrozole was found to be as effective as other methods of ovulation induction.[168]

The usual dose for letrozole ovulation induction is 2.5 mg on cycle days 3-7. However, the optimal dosage and length of administration is under investigation.[169, 170] Aromatase inhibitors are generally well tolerated. The main side effects are hot flushes, gastrointestinal events (nausea and vomiting), headache, back pain, and leg cramps. These adverse effects were reported in older women with advanced breast cancer who were given the drugs on a daily basis over several months. In younger women taking them at lower doses for a short period of time, fewer adverse effects are noted.

The use of aromatase inhibitors for ovulation induction in premenopausal women is controversial due to the possibility of fetal toxicity and fetal malformations raised by one abstract.[171] However, 2 subsequent publications have shown no evidence of fetal malformations with the letrozole and no difference in birthweight compared with spontaneous conceptions.[172, 173] Furthermore, based on the half-life of each drug, administration in the early follicular phase should result in clearance of the aromatase inhibitors before implantation takes place.

Human menopausal gonadotropins
Crowe discovered that the go**ds were under the control of the anterior hypophysis.[174] Zondek and Aschheim discovered that FSH and LH were responsible for the development of the go**ds in immature animals and confirmed Crowe's work.[134, 135] In the 1930s, ovulation induction was attempted by using gonadotropins from a mare, but its use was discontinued because of the development of antibodies.[175, 176]

Borth et al demonstrated the effect of FSH and LH extracted from menopausal urine.[177, 178] Gemzell reported the first ovulation induction using human pituitary gonadotropin in 1958, and the first pregnancy was reported in 1960.[179, 180] Lunenfeld reported preliminary results using hMG; however, in 1963, it was definitely established as a real ovulation induction agent.[181, 182, 183]

hMG (Repronex, Menopur) contains 75 U of FSH and 75 U of LH per mL, although the concentration may vary among batches (ranges from FSH at 60-90 U and LH at 60-120 U). In the 1980s, a pure form of FSH became available. Bravelle contains 75 U of FSH. The new generations of available gonadotropins are produced by genetically engineered mammalian cells (ie, Chinese hamster o***y cells), in which the gene coding for the alpha and beta FSH subunits has been inserted (Gonal F and Follistim).[184] Recombinant LH may be added to recombinant FSH protocols as an alternative, particularly useful in patients with hypothalamic amenorrhea.

The administration of hMG and its derivatives should be under the direct supervision of a reproductive endocrinologist. An ultrasonography unit and an endocrine laboratory capable of performing daily determinations of E2, FSH, and LH are necessary.[185, 186, 187, 188, 189]

Multiple adverse effects and complications may occur during the use of the gonadotropins, including (1) multiple pregnancy (24-33%), (2) ectopic pregnancy (5-8%), (3) miscarriages (15-21%), (4) ovarian torsion and rupture, and (5) ovarian hyperstimulation syndrome, which is the most severe.[190, 191] Whittemore et al, using a large combined data set derived from case-controlled studies in the United States, showed that the increase of ovarian cancer associated with infertility might be due to the use of fertility drugs.[192]

Ovarian hyperstimulation syndrome is an iatrogenic condition that occurs in patients undergoing ovulation induction with hMG or controlled ovarian hyperstimulation (COH) for assisted reproductive technologies. The incidence rate fluctuates from 0.1-30%. The pathophysiology of the disease is not well understood, but a massive extravascular accumulation of fluid occurs that is associated with a severe depletion of the intravascular volume responsible for dehydration, hemoconcentration, and electrolyte imbalance (ie, hyponatremia, hyperkalemia).[193] Ovarian hyperstimulation syndrome can be mild, moderate, or severe.[194]

Mild ovarian hyperstimulation syndrome is characterized by ovarian enlargement (up to 5-12 cm in diameter), minimal ascites, and weight gain of less than 10 lb. Moderate ovarian hyperstimulation syndrome is characterized by ovarian enlargement (5-12 cm in diameter) moderate ascites, nausea, vomiting, abdominal discomfort, and weight gain greater than 10 lb. Severe ovarian hyperstimulation syndrome is characterized by easily palpable ovaries, severe ascites, nausea, vomiting, diarrhea, shortness of breath, hydrothorax, peripheral edema, oliguria, hemoconcentration (eg, hematocrit level >48% and hemoglobin level >16 g), and creatinine level greater than 1.6 mg/dL. Renal failure and thrombosis can occur if the patient is not treated correctly.[195]

Some patients have a greater risk of developing ovarian hyperstimulation syndrome. They are usually young patients with a history of polycystic ovarian syndrome or oligo-ovulation who responded with elevated E2 levels (3000 pc/mL) and multiple follicles (>15) and patients in whom the ovulation has been triggered by the administration of exogenous hCG.[196, 197]

Ovarian hyperstimulation syndrome usually has 2 phases. The first phase develops between the second and seventh day after ovulation, and the second phase only occurs if the patient becomes pregnant. Ovarian hyperstimulation syndrome is self-limited, and the symptoms subside within 2-6 weeks.[198]

Patients with mild and moderate ovarian hyperstimulation syndrome are treated at home with bedrest and strict control of fluid intake and output. If a weight gain greater than 2 lb occurs, the patient should be evaluated to determine if hospitalization is required.

Patients with severe ovarian hyperstimulation syndrome are often hospitalized and confined to bed, with strict control of fluid intake and output. Intravenous fluids (ie, isotonic sodium chloride solution) must be administered until hemodilution is achieved. If the urinary output remains low, albumin 25% (50 mL/h IV for 4 h) has been effective in promoting diuresis. Transva**nal or abdominal paracentesis should be performed if the patient becomes uncomfortable. Thoracentesis is rarely indicated in cases of pleural effusion. Because of the risk of thrombosis, heparin (5000 U SC q12h) is recommended.[195] Some have had success treating severe ovarian hyperstimulation syndrome on an outpatient basis by performing aggressive transva**nal paracentesis with good outcomes.[199]

hMG and its derivatives are indicated for ovulation induction in patients with primary amenorrhea due to hypopituitarism and in patients with secondary amenorrhea who did not respond to CC ovulation induction. For the past 20 years, hMG and its derivatives have been the first choice for controlled ovarian hyperstimulation in assisted reproductive technologies.

Gonadotropin-releasing hormone
Synthetic GnRH (eg, Factrel, Gonadorelin, Lutrepulse) has a chemical composition similar to native GnRH and is indicated for patients with hypothalamic dysfunction, especially those who do not respond to CC.[200, 201] Although quite effective, it is not available in the United States due to lack of use and low demand. This drug is administered in a pulsatile fashion every 60-120 minutes, intravenously or subcutaneously using a delivery pump. The starting dose is 5 mcg per pulse intravenously or 5-25 mcg subcutaneously. The administration on GnRH should be extended throughout the luteal phase, or this should be supplemented with the administration of exogenous hCG.[202]

Monitoring folliculogenesis is simpler than using hMG. Because ovarian hyperstimulation syndrome does not occur, the patient's response is slow. In most cases, only 1 follicle is recruited and develops until ovulation. A urinary LH kit is a practical way to monitor these patients. Pelvic ultrasonography can be used once a week until the dominant follicle is detected; once this occurs, ultrasonography can be used more frequently until ovulation occurs. Determination of serum E2 and LH levels can also be performed.[203]