History of Present Illness

A 32-year-old nulligravid woman presents to your office with her husband for infertility. They have been trying to conceive for two years without success, despite having intercourse two to three times per week. They have not sought care until now because their insurance does not cover infertility services and they are concerned about the cost of care.

The patient reports menarche at age 14, with fairly regular menses as an adolescent and young adult, but does report she would skip a menstrual cycle one or two times per year. She started on oral contraceptives at age 22 years. Since stopping her birth control pills two years ago, she reports bleeding every 45–60 days that lasts for 3–10 days. She notes moliminal symptoms prior to about half of those bleeding episodes and denies significant dysmenorrhea or dyspareunia. She also reports a gradual increase in her weight in the past five years as well as increasing fatigue. She denies unusual headaches, hirsutism, galactorrhea, heat or cold intolerance, diarrhea, or constipation. She has no history of sexually transmitted diseases, pelvic inflammatory disease, or abnormal pap smears, and her co-testing was negative two years ago.

Her medical and surgical histories are otherwise unremarkable. She denies family history of infertility or premature ovarian insufficiency. She drinks one alcoholic beverage on the weekends and does not smoke. She works part-time as a teacher. She does not regularly exercise but walks 15 minutes to and from work. She has no allergies and is taking prenatal vitamins. Her last menstrual period was five weeks ago.

Her husband is 34 years old and has not fathered any children. He has no significant medical or surgical history and takes no medications. He works at a construction company and smokes about two to four cigarettes per week and drinks less than two alcoholic beverages per week.

Physical Examination

Body mass index

29 kg/m²

Blood pressure

126/84 mmHg

General

Alert, oriented

Skin

No rashes, skin changes, or acne

Breasts

No lymphadenopathy, no masses or nipple discharge

Neck

Thyroid without masses

Chest

Heart regular rate and rhythm, lungs are clear to auscultation

Abdomen

Soft, non-tender, no hepatosplenomegaly, no masses appreciated

Urine pregnancy test

Negative

How Would You Manage This Patient?

Traditionally, patients with infertility should have a workup that includes an assessment of ovulatory function, a semen analysis, and an assessment of tubal patency.

This patient has a clinical history suggestive of ovulatory dysfunction; therefore, a thyroid-stimulating hormone (TSH) and prolactin were ordered to evaluate for underlying causes. It was recommended that her husband have a semen analysis to rule out male factor as a cause. Assessment of tubal patency with a hysterosalpingogram (HSG) was discussed; however, since the patient has no risk factors for tubal disease, and cost was a significant concern to the patient and her husband, it was decided to hold off on that, pending the remainder of her workup.

Her labs revealed a normal prolactin, an elevated TSH at 8.2 IU/mL, and a low free T4 of 0.5 ng/mL, consistent with a diagnosis of hypothyroidism. The semen analysis was normal. She was started on levothyroxine and counseled regarding weight loss for overall improvement of her health. She and her husband were also counseled on smoking cessation and limiting alcohol use. After six months, she lost 25 lb, her TSH had normalized, and she reported resumption of regular menses. She conceived three months later.

Cost-Conscious Infertility Evaluation

Diagnostic evaluation for causes of infertility is indicated after 12 months of regular unprotected intercourse when the female partner is under 35 years of age and after six months if the female partner is 35 years or age or older. Eighty-five to ninety percent of apparently normal couples will conceive in the first 12 months [1]. Evaluation is warranted earlier if the couple suffers conditions known to limit fertility such as advanced endometriosis, oligomenorrhea or amenorrhea, known or suspected uterine or tubal disease, or suspected male subfertility. Evaluation and treatment should occur immediately in women over 40 years of age [2].

Ovulatory dysfunction is one of the most common findings in infertile women; therefore, ovulatory status needs to be assessed in each patient. Often, a thorough menstrual history is all that is needed. A patient with monthly menses and moliminal symptoms is considered ovulatory, while those with amenorrhea or oligomenorrhea are unlikely to be ovulating regularly. For those patients in whom ovulatory status is unclear, further testing would be indicated. A simple option is to obtain a midluteal progesterone. This should be scheduled for a week prior to anticipated menses, which would be dependent on the individual patient’s cycle length. A progesterone level >3 ng/mL indicates ovulation. Another option is to have the patient use an ovulation predictor kit [5]. It is important to stress to the couple that the color change indicates the luteinizing hormone (LH) surge, which precedes ovulation by 24–48 hours. Intercourse is recommended the day of the LH surge or the following day. Ovulation predictor kits can vary in price but typically cost anywhere from $10 to $50 for a month’s supply, whereas a single progesterone level would be around $50–$100 if paid out of pocket.

Ovulatory dysfunction, if identified, warrants further investigation to determine a possible etiology and guide treatment. Without going into a thorough discussion, it is similarly important to identify a structured and basic evaluation of oligomenorrhea (<9 cycles / year) or amenorrhea. A TSH and prolactin should be obtained to rule out thyroid disorders and hyperprolactinemia. If these are normal, it would be reasonable to order a serum follicle-stimulating hormone (FSH), particularly if there is concern for primary ovarian insufficiency. These tests are close to $100 each. Polycystic ovarian syndrome is often considered in this evaluation and should be further investigated, especially if the patient reports symptoms of hyperandrogenism such as hirsutism and acne [8].

It is estimated that approximately 25–35 percent of couples suffer male factor infertility [1,3]. Formal recommendations are for a complete medical history of the male partner and at least one semen analysis. There is a great deal of intraindividual variation in the test, and a repeat semen analysis to confirm an abnormality can be useful. As the provider ordering the semen analysis, one should counsel the male partner that the test should be performed after 2–5 days of abstinence. Ideally, the specimen is collected by masturbation at the laboratory in which the testing is performed. The specimen can also be collected in a specialized condom and brought to the lab within an hour [4]. The out-of-pocket costs for a semen analysis are typically equivalent to that of the individual blood tests (~$100). When cost is a significant concern, a home semen analysis kit can be purchased in drug stores or online for $30–$50, and these have a reported accuracy of >98%. Despite its inherent limitations, many providers consider semen analysis an important step prior to moving forward with the treatment of the female partner, given the relatively high prevalence of male factor infertility. On the other hand, couples in which the male partner is healthy, is without risk factors, and has fathered a child in the past may choose to forgo semen analysis initially.

Testing for tubal patency is also a conventional part of an initial infertility evaluation. The most commonly performed test is the HSG due to it being both diagnostic and possibly therapeutic, as there is evidence of increased pregnancy rates following HSG [6]. In addition to showing both proximal and distal tubal occlusion, HSG can detect salpingitis isthmica nodosa and intracavitary abnormalities, such as submucosal fibroids and mullerian anomalies which can affect fertility. Often, further studies are indicated if the HSG is abnormal, such as a pelvic ultrasound to assess fibroids, a 3-D pelvic ultrasound or MRI to further characterize a mullerian anomaly, or even laparoscopy. In a patient in whom laparoscopy is planned, for example those in whom there is concern for endometriosis, a chromopertubation can be performed at the time of surgery, obviating the need for HSG [5]. Unfortunately, the cost of an HSG can be prohibitively high, ranging between $400 and $7,000, depending on the institution. In this case, in the absence of risk factors, it is possible that this test would be of limited value. It may be appropriate to address a finding of ovulatory dysfunction initially and proceed with HSG if the subfertility persists.

The American College of Obstetrics and Gynecology and the American Society for Reproductive Medicine suggest ovarian reserve testing on women over the age of 35 years who present for fertility evaluation as well as others with increased risk of decreased reserve, such as those with a history of cancer or medical problems treated with gonadotoxic therapy, surgery to the ovaries, or pelvic radiation [7]. It is inferred that ovarian reserve testing should not be performed as initial screening in all patients who present with inability to conceive. There are multiple tests for decreased ovarian reserve. The most appropriate initial tests are a basal (“day 3”) FSH and estradiol. Elevated FSH of 10–20 IU/L is associated with poor response to ovarian stimulation. Estradiol is often added to the FSH to confirm the value of the FSH. An elevated estradiol (>80pg/mL) can suppress a rising FSH and result in a false negative FSH if it is evaluated alone. An alternative ovarian reserve test is a single measure of the anti-Mullerian hormone (AMH), which reflects the size of the primordial follicle pool. The benefit of this test is that it can be drawn at any time during the menstrual cycle as it has shown little intercycle and intracycle variability [7]. Additionally, the AMH, which costs approximately $100, is less expensive than the FSH and estradiol together (~$200), suggesting this may be the more ideal test when cost is a concern.

Features of the history or physical exam concerning for endometriosis are often identified. Treatment of endometriosis implants with ablation or resection, even in early disease, can improve pregnancy rates [9]. Likewise, the diagnosis of endometriosis will dictate infertility treatment options and is therefore important to make. While surgical evaluation should be performed in women with symptoms concerning for endometriosis or other pelvic / peritoneal pathology, diagnostic laparoscopy for asymptomatic women as part of a standard evaluation is of low yield and should not be a first step [5,9].

Key Points

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  Diagnostic evaluation should be performed after 12 months of inability to conceive in patients <35 years of age, after six months in patients age 35 years or older or with obvious risk factors, and immediately in women over age 40 years.

  
  
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  Ovulatory status should be assessed in every patient and can frequently be done with history alone. Further laboratory testing should be dictated by these findings.

  
  
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  Semen analysis, HSG, and ovarian reserve testing can be performed in a stepwise fashion, targeting the most likely potential etiologies identified on history and physical exam first, with further workup only if infertility persists.

  
  
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  Ovarian reserve testing need not be performed on every patient but limited to those >35 years or with significant risk factors for decreased ovarian reserve.

  
  
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  Diagnostic laparoscopy may be indicated for patients in whom endometriosis or other peritoneal pathology is suggested by history or exam, but should not be performed on all patients.

History of Present Illness

A 33-year-old woman, gravida 0, para 0, presents with her husband for an infertility evaluation after trying to conceive for 18 months without success. Her husband has not fathered a pregnancy before. She has a history of regular menstrual cycles and has used ovulation predictor kits, which turn positive around cycle days 14–16. They time intercourse appropriately. Her family medicine physician had ordered thyroid-stimulating hormone (TSH), prolactin, follicle-stimulating hormone (FSH), and semen analysis, which were normal.

Her past gynecologic history is notable for chlamydia infection three years ago and pelvic inflammatory disease (PID) with a gonorrhea infection ten years ago. She and her partner were treated. Her cervical cancer screening tests have been normal and her last one was six months ago. She and her husband are otherwise healthy and deny smoking, alcohol, or drug use. She is taking prenatal vitamins. The patient and her husband’s family histories were unremarkable for any significant medical or genetic disorders.

To complete her infertility evaluation, she had a hysterosalpingogram (HSG) ordered with doxycycline prophylaxis, given her history of PID.

Physical Exam

General appearance

Well-developed, well-nourished woman in no discomfort

Temperature

37.6°C

Pulse

80 bpm

Blood pressure

110/60 mmHg

Respiratory rate

18 respirations/min

Height

5 feet 4 inches

Weight

150 lb

BMI

25.7 kg/m²

Abdomen

Soft, not tender, not distended, no guarding, no rebound

External genitalia

Unremarkable

Vagina

White and clear discharge with stretchy clear mucus

Cervix

Nulliparous. No bleeding or discharge. Small amount of ectropion noted. No cervical motion tenderness

Uterus

Anteverted, mobile, normal size, no tenderness

Adnexa

Fullness noted bilaterally. No tenderness

Laboratory Tests

Gonorrhea and chlamydia nucleic acid amplification tests negative

Hysterosalpingogram

Normal uterine cavity and bilateral hydrosalpinges. No tubal spill (Figure 53.1).

Pelvic ultrasound

Hypoechoic tubular cysts with an incomplete septum consistent with bilateral hydrosalpinges (Figure 53.2).

Figure 53.1 Hysterosalpingogram. The white arrows point to the white oblong, tubular structures on each side of the x-ray, which are bilateral hydrosalpinges.

Figure 53.2 Ultrasound of hydrosalpinx. The white arrow points to an incomplete septum in a thin-walled fluid-filled serpiginous tubal shaped structure, which are ultrasound characteristic findings for hydrosalpinx.

How Would You Manage This Patient?

This patient has bilateral hydrosalpinges noted on HSG (Figure 53.1) and pelvic ultrasound (Figure 53.2). These hydrosalpinges are large and no mucosal folds are visible. It is unlikely that surgical repair would result in functional tubes. The couple was counseled regarding the imaging findings, including the impact of these large hydrosalpinges on their fertility and the options available. Recommendation was made to remove the tubes or ligate them laparoscopically, and then proceed with in vitro fertilization (IVF) to maximize the chance of pregnancy.

Tubal Factor Infertility

Tubal disease accounts for approximately 25–40 percent of female factor infertility [1–4]. Over 50 percent of tubal disease is due to salpingitis [1]. Salpingitis typically results from sexually transmitted pelvic infections causing PID. Other causes of tubal occlusion include peritonitis, inflammatory changes from endometriosis, appendicitis, Crohn’s disease, or ulcerative colitis, and adhesions or damage from other pelvic surgeries including ectopic pregnancy, ovarian cystectomies, abdominal myomectomy, or multiple laparotomies.

Tubal factor infertility may be due to occlusion of the tubes either proximally or distally. The tubes are traditionally evaluated during the initial infertility workup with a HSG or saline infusion sonohysterogram with agitated saline or ultrasound contrast (use of the latter is off FDA label). The reliability of these tests is quite good for confirming patency. Proximal tubal obstruction may not be as reliably detected as distal. Repeating an HSG to reevaluate fallopian tubes with suspected proximal occlusion a month later demonstrates tubal patency in about 60 percent of cases [1]. Uterine spasm can make the fallopian tubes appear occluded on HSG. The proximal fallopian tube has a very small diameter at the cornual portion where it traverses through the myometrium. The spasm may not be present on repeat testing. Alternatively, minor debris within the tube may have been partially cleared during the initial HSG. Proximal tubal occlusion can be treated with tubal cannulation with a coaxial system either during fluoroscopy in the radiology suite or intraoperatively with combined laparoscopy and hysteroscopic tubal cannulation. Tubal cannulation has 60–95 percent success in resolving the obstruction with about 50 percent of patients conceiving and one-third re-occluding [1]. Tubal perforation is reported in 3–11 percent of cases but has no clinical consequences. Occasionally, correcting a proximal tubal occlusion will reveal an additional distal tube occlusion, which has a poor prognosis.

Mid- and distal tubal occlusions are not due to spasm since there is minimal muscle surrounding the tube and no myometrial tissue. The diameter of the mid- and distal tube is larger than the proximal tube. Laparoscopy with chromopertubation performed under general anesthesia is considered the gold standard to assess for tubal patency. Distal tubal obstruction occurs with hydrosalpinges. A hydrosalpinx is a dilated, sterile serous fluid-filled fallopian tube. On HSG, a hydrosalpinx appears as a collection of contrast material in an oblong or tubular structure with blunted, rounded ends. Hydrosalpinges may also be detected on 2D ultrasound, saline infusion sonohysterogram, or transvaginal hydrolaparoscopy with chromopertubation [1].

Hydrosalpinges appear to have negative impact on fertility beyond simply obstructing the tubes, and patients undergoing IVF with untreated hydrosalpinges have a 50 percent reduction in pregnancy rates [1, 2]. In a meta-analysis of 11 studies with more than 6,700 IVF cycles, women with untreated hydrosalpinges not only had a 49 percent reduction in pregnancy rates, but also had a two- to threefold increase in miscarriage rates when compared to controls with tubal factor infertility without hydrosalpinges [10]. The reduced pregnancy rate may be caused by fluid from the hydrosalpinx passing into the uterine cavity, where it may be embryotoxic, may flush the embryo out of the uterine cavity, or may impair uterine receptivity.

Treatment for Hydrosalpinges

Four randomized controlled trials demonstrated that in women with bilateral hydrosalpinges, bilateral laparoscopic salpingectomy improved pregnancy rates over untreated subjects. Three of these trials showed improvement in both ongoing pregnancy and live birth rates [8]. The Cochrane Database review similarly reports improved pregnancy rates when laparoscopic salpingectomy or ligation (tubal occlusion) is performed prior to IVF [7]. Studies are less clear as to whether women with a unilateral hydrosalpinx should undergo a salpingectomy. The American Society of Reproductive Medicine Practice Committee Opinion concluded that unilateral salpingectomy for unilateral hydrosalpinx improves IVF pregnancy rates and recommends unilateral salpingectomy for unilateral hydrosalpinx. It concluded that the spontaneous pregnancy rate is 88 percent within five to six months of surgery with no ectopic pregnancies, but the duration of improved fertility may be as long as three years [1].

Hydrosalpinges are usually removed by laparoscopic salpingectomy. Most commonly, electrocautery is used to separate the tube from the uterus. The tube is excised along the mesosalpinx as close as possible to the tube to avoid compromising the vasculature within the mesosalpinx, which also supplies the ovary. The tube should be excised in its entirety. If there are significant pelvic adhesions or other technical obstacles to salpingectomy, it is reasonable to ligate the tubes at the junction of the tube and uterus, which will block seepage of fluid into the uterine cavity. Some advocate creating large fenestrations in the tube to allow for leakage of the tubal fluid into the abdominal cavity to prevent further distension of the tube and possible future pelvic pain [1].

Ovarian reserve after salpingectomy has been studied. A meta-analysis of 12 retrospective and 6 prospective studies included 1,482 patients with 657 having undergone salpingectomy and 825 not [6]. Their findings showed no difference in estradiol levels, total gonadotropin used in stimulation, or the number of oocytes retrieved. One randomized trial found that use of bipolar cautery was associated with lower ovarian volumes and antral follicle counts, but mechanical clips did not have this effect [1]. Several studies showed no compromise of ovarian reserve with laparoscopic tubal ligation done with bipolar cautery [1]. Carefully performed salpingectomy or ligation does not appear to have a significant impact on ovarian reserve in patients undergoing IVF.

Alternative Approaches

Occasionally, there are situations when laparoscopy may be contraindicated or an abdominal approach may need to be avoided due to concerns for operative morbidity like severe pelvic adhesions. In these situations, alternatives include hysteroscopic tubal occlusion or ultrasound-guided aspiration of the hydrosalpinx. Hysteroscopic tubal occlusion may be performed with an Essure device. Use of Essure to occlude the proximal end of the tube with hydrosalpinx was first reported in 2005 and resulted in a successful pregnancy. Since that time, there have been several studies showing improved pregnancy rates with hysteroscopic proximal tubal occlusion (38.6 percent pregnancy rate and 27.9 percent live birth rates) [2]. Typically, IVF is delayed 3–6 months after the Essure is placed to allow inflammation to resolve and proximal occlusion to be complete. Only 17 percent of coils are completely encapsulated with adhesions within 1 year and 25 percent within 3.5 years [1]. The uterine cavity is often not evaluated between tubal occlusion and performing IVF, so it is unknown if waiting until the adhesions wall off the proximal tubal occlusion coils improves pregnancy rates. Increased incidence of miscarriage and accumulation of uterine fluid has been reported [3].

Ultrasound-guided aspiration of the hydrosalpinx is typically performed at the time of oocyte aspiration. In some patients, the tubal fluid does not recur after aspiration. Others reaccumulate either early or late. Women with tubes that do not reaccumulate fluid or where the fluid returns late (two or more weeks after aspiration) have similar pregnancy rates to those who have had a salpingectomy [6, 9]. Those with rapid reaccumulation of fluid or fluid that collects in the uterine cavity prior to the embryo transfer did not conceive [6, 9].

Patients with mild hydrosalpinx (<3 cm), minimal or no filmy adnexal adhesions, and normal-appearing endosalpinx with preserved mucosal folds on HSG are considered good prognosis. These women will have better pregnancy rates with IVF than women with more significant tubal disease. Tubal repair surgery, such as laparoscopic neosalpingostomy or fimbrioplasty, may be effective. These techniques focus on opening the tube at the fimbrial end, everting the fimbria, and securing them with suture or electrocautery on the tubal serosa [1]. Pregnancy rates are lower after tubal surgery than IVF [5]. Surgery will delay conception and is associated with twice the ectopic pregnancy rate of IVF. In a randomized trial, there were no differences between laparotomy and laparoscopy for pregnancy or ectopic pregnancy rates. Consequently, laparoscopic approaches are recommended. After tubal reconstruction, the pregnancy rate is about 35 percent within one year and 58 percent in two years. The ectopic pregnancy rate is 3.9–5.0 percent. In women with poor prognosis or combined proximal and distal tubal occlusion, the pregnancy rate is 0–22 percent and ectopic rate is 0–17 percent [1]. Tuboplasty is not appropriate for poor prognosis patients or women with combined proximal and distal occlusion.

Key Points

• 
  

  Salpingectomy is recommended before IVF and gonadotropin therapy for women with bilateral hydrosalpinges. There appears to be no significant impact on ovarian reserve.

  
  
• 
  

  The data are more limited for women with unilateral hydrosalpinx, but salpingectomy is generally performed.

  
  
• 
  

  Alternative approaches such as hysteroscopic proximal tubal occlusion and ultrasound-guided hydrosalpinx aspiration appear to have better pregnancy rates than no treatment, but not as good as salpingectomy or ligation prior to assisted reproductive technologies (ART).

  
  
• 
  

  In good prognosis cases, tuboplasty can be considered, but it appears to have lower success rates and higher ectopic rates than IVF. Tuboplasty should not be performed in women with significant tubal disease.