Obstetric and Gynecologic

Complications in Gynecological Oncology

2009-04-09T04:10:00.000-07:00

This quote provides a very good introduction to this chapter. Complications occur in all forms of gynecological surgery. They can be reduced by a variety of strategies. The view expressed by the consultant quoted above may reﬂﬂect a number of points. First, the consultant’s surgical workload or practice may be too small. Unless complications occur frequently, the practitioner with a small practice will not see many problems within an assessable time frame. Therefore, there will be a lack of insight with regard to these problems or even a selective memory, leading the practitioner to believe that his or her surgeries have few or no complications. This trend has been compounded in the National Health Service (NHS) by poor data collection and no agreement regarding the minimum data set relating to complications. Audit of outcomes and complications is sporadic and usually covers only a short time period. This deﬁﬁcit also leads to complacency with respect to complications.

In gynecological oncology surgery, there are some data relating to complications. Increasingly, we are dealing with a centralized service following the introduction of the Improving Outcomes Guidance in England and Wales [1]. This centralization and the introduction of mandatory minimum data-set collection will lead to more information about complications and should reduce the number of practitioners who subscribe to the opinion voiced in this chapter’s opening quote.

Radical Cancer Surgery

The aim of radical cancer surgery is in the ﬁﬁrst instance curative. In ovarian cancer, surgery is diagnostic (providing histological material), needed for staging, and also therapeutic [2], regardless of the ﬁﬁnal stage. In endometrial cancer, the surgery is the cornerstone of treatment even with advanced disease, providing information relating to stage as well [3]. In cervical cancer, surgery is reserved for curative intent in patients with early disease. In patients with recurrent cervical disease, surgery may be curative with exenteration [4] but is more often palliative to control symptoms.

Complications of Radical Surgery

Anesthetic and Perioperative Complications

The outcome of surgery depends in part on the patient’s ﬁtness (see Figure 2.1). The patients we treat who have gynecological cancer usually comprise an older population than patients with other gynecological conditions. Considerable comorbidity is present in the gynecological cancer population; this comorbidity in itself leads to a higher rate of complication. In comparing outcomes, including hospital stay, these comorbidities should be taken into account. This may be addressed using an evaluation tool such as the “adult comorbidity evaluation-27” sheet [5], which may be used for the minimum cancer data set.

Perioperative death (within 24 hours) was 8.8. per 10,000 anesthesia administrations, with 85% of the deaths related to the patient’s comorbidity. Thus, selection of the appropriate operation for each patient is important. In the group of patients who died as a result of anesthetic-related problems, 25% were inadequately prepared for surgery [6].

Appropriate liaison with consultant anesthetists and suitable preoperative preparation of patients with gynecological cancer lead to better outcomes. The primary debulking surgery required for advanced ovarian cancer or the management of the patient for interval debulking surgery is not comparable to routine benign gynecological surgery, and therefore there is an intraoperative requirement for epidural usage, central venous and arterial monitoring, and postoperative high-dependency or intensive-care support.

Risk reduction relating to anesthesia can be achieved by the following practices:

The use of an appropriately skilled anesthetist providing an apt preoperative assessment

The use of intraoperative regional anesthesia in addition to general anesthesia, which leads to reduced amount of central sedation,

2. Complications in Gynecological Oncology

reduced effect on the gut motility postoperatively, and reduced thrombosis risk, as well as excellent postoperative analgesia

• Good postoperative care, with access to correctly staffed high-

dependency and/or intensive care In the gynecological oncology center, the anesthetist is an integral part of the multidisciplinary team.

Infection

In gynecological oncology, patients are at risk of infection in the chest, in the pelvis/intraabdominal region, in the urinary tract, at the wound site, and at sites of intravenous and arterial lines. Any prophylactic regime is effective in reducing postoperative infective complications [7]. It is important that the regime be given at the appropriate time. We have used a nurse-based “patient group directive” to ensure that all women undergoing surgery, whether elective or emergency, are covered by antibiotic prophylaxis. As the majority of our patients are more than 60 years old, we avoid the use of cephalosporins, as this can predispose toward pseudomembranous colitis [8]. Our patients receive metronidazole (500 mg IV), gentamicin (120 mg IV), and benzyl penicillin (1.2 g IV) with induction of anesthesia. We omit the penicillin if the patient is allergic. We see very few cases of chest infection in our group due to the use of regional anesthesia and active pre- and postoperative physiotherapy.

Thrombosis

Patients with gynecological cancer are at increased risk of thrombosis resulting from the malignancy and the effects of pelvic surgery. Many patients have had decreased mobility prior to surgery as a result of massive ascites. The ascites, combined with a pelvic mass, which can compress the venous return from the legs, causes the woman with gynecological cancer to present a special risk for thromboembolism. In addition, many women with gynecological cancer have a morbidly increased body mass index and thus are at risk of embolism. Following gynecological oncology surgery, the incidence of deep vein thrombosis without prophylaxis is in excess of 40% [9].

Therapeutically, a number of gynecological oncology patients are taking agents that lead to an increased risk of thromboembolism. While conventional hormone replacement therapy (HRT) is well known to predispose to thromboembolism, patients taking tamoxifen have a greater risk of thrombosis and are therefore advised to stop taking it 2 weeks before surgery. This point is important, as there is an increased number of breast cancer patients who opt for surgical ablation of their ovaries as part of their breast cancer management.

We use low-molecular-weight heparin (40 mg subcutaneously) on a daily basis. This regimen is given at 18:00 hours on admission and so will not interfere if an epidural is used the following morning. In addition, patients wear graduated stockings and are well hydrated. We prefer to use regional anesthesia in addition to the general anesthesia, as this has the positive beneﬁﬁt of reducing thrombosis. Calf stimulation is also used in the operating theater, although the evidence for this procedure’s beneﬁﬁt is not conclusive. We continue the low-molecular-weight heparin until the patient is discharged from the hospital.

In patients with signiﬁﬁcant deep vein thrombosis, we also consider using an inferior vena caval umbrella ﬁﬁlter inserted under radiological control. Its use greatly reduces the risk of fatal pulmonary embolus, which is especially marked when there is bilateral iliac venous thrombosis associated with a pelvic mass.

Hemorrhage and Transfusion

During extensive surgery for advanced malignancy, patients are at signiﬁﬁ cant risk for intraoperative or primary blood loss. We routinely crossmatch 4 units of blood for patients undergoing ovarian cancer surgery. With patients undergoing interval debulking surgery, we often anticipate an anemia due to the cancer and the effect of chemotherapy. Patients will often be transfused as the operation starts. Our anesthetic team prefers this to transfusion on the day prior to the operation. As these patients are operated on in the window between cycles of chemotherapy, we do not delay the patient as one might do other patients with anemia for a benign operative indication. Secondary hemorrhage occurs rarely and is usually associated with a slipped ligature or unrecognized bleeding point. Often there is a large raw area following tumor resection, and we ﬁﬁnd that lavage with hot (30˚C–40˚C) water (not saline) allows identiﬁﬁcation of bleeding points.

Unfortunately, we do not have easy access to erythropoietin for our chemotherapy patients in the NHS. This subcutaneous treatment can be useful to maintain the hemoglobin during chemotherapy and reduce the need for transfusion prior to interval debulking surgery.

Damage to Organs

Radical gynecological surgery aims to remove as much of the disease as required, including a margin of normal tissue. In cervical cancer surgery, this leads to Wertheim’s approach, whereby the ureter, bladder, and bowel are dissected free from the cervical cancer. The incidence of ﬁﬁstula rate is reported as between 1% and 6% for this surgery. During lymphadenectomy, there is a risk of major vessel damage. Vascular injury associated with lymphadenec

2. Complications in Gynecological Oncology

tomy in endometrial cancer occurred in 0.7% of the cases; however, this was satisfactorily managed through adequate surgical training and experience of staff within the unit [10]. During ovarian surgery, the disease is usually con

ned to the peritoneal cavity, and signiﬁﬁcant removal of disease can be achieved by peritoneal stripping. Rectal resection with primary anastomosis for clearance of pelvic disease is advocated by some. The acceptable level for anastomotic leak should be equivalent to that for rectal surgery. In the cancer center, we have access to many specialists who can provide intraoperative advice regarding organ injury. This is very helpful when considering injuries, which fortunately are very rare.

Wound dehiscence and hernias are relatively uncommon but are associated with cancer cachexia and midline incisions.

Psychological Complications

The patient diagnosed with gynecological cancer often responds by wanting everything possible done to remove the cancer. While a postmenopausal woman, who has completed her reproductive life, may view a hysterectomy as the removal of an organ that has “turned bad,” a young woman may have a very different viewpoint. This is especially marked for those women whose diagnosis is made through screening. The woman diagnosed through screening has never had any symptom or sign of the disease and relies on the medical service for making the diagnosis as well as treating the cancer. The patient then has to live through the life-threatening illness, with major surgery and recovery, never having been “sick” in the ﬁﬁrst place.

Although the majority of women with gynecological cancer have already completed their families or are postmenopausal, a small group of younger gynecological cancer patients still have fertility needs. This situation is also pertinent for those patients with breast cancer. Preservation of fertility potential can pose a signiﬁﬁcant problem. Germ cell ovarian cancer can be treated with conservative surgery, as this disease needs treatment with chemotherapy. Recognition of the potential of this condition is imperative, as germ cell ovarian cancer is associated with a young age group and an overall better survival rate. As there has been a tremendous increase in cervical intraepithelial neoplasia (CIN), a number of young women are requiring many cervical treatments. Excisional treatments to the cervix lead to earlier delivery. Consideration must be given to assisted fertility techniques for collection of oocytes or embryos for these young women, although there is often limited time for this treatment.

Radical vulval surgery is associated with severe changes to body image. This has prompted the move to the triple incision, with which we try to reduce the morbidity of the traditional radical en bloc vulvectomy. We aim to perform a wide local excision with a 2 cm macroscopically clear margin from the tumor. This reliably leaves an 8 mm pathologically clear margin, which is associated

with minimal risk of local recurrence. The inguino-femoral lymphadenectomy results in a signiﬁﬁcant risk of lymphedema, which is ugly and has its associated comorbidity. In the early postoperative period, wound healing is compromised by infection and/or formation of lymphocysts in 20%–30% of patients, while in the long term, lymphedema of the legs with increased risk for cellulitis is reported in 10%–70% of patients.

Sexual dysfunction has been measured in up to 80% of women undergoing gynecological cancer surgery [11].

How to Reduce Complications Further

Complications associated with gynecological cancer surgery can be reduced by addressing several areas of practice, starting with the patient and leading through aspects of the disease, operation, surgeon and his or her team, and therapy.

Through education, patients can be advised about disease-reduction activity. In gynecological cancer, this is the use of the oral contraceptive pill for 5 years, which leads to a 50% reduction in ovarian cancer risk, albeit with an increased risk of cervical cancer. The use of tamoxifen leads to a signiﬁﬁcant reduction in breast cancer, but its long-term usage is associated with a signiﬁﬁ cant increased risk of endometrial cancer. The move to the aromatase inhibitors for breast cancer will lead to much less endometrial disease. Uptake of appropriate screening methods that have been validated is important. We have seen a signiﬁﬁcant reduction in cervical cancer since the active call/recall system for cervical screening by primary care was introduced in 1988. Cervical cancer has become a rare cancer in the last decade in the United Kingdom, a situation that has not been mirrored in the rest of Western Europe. The role of laparoscopic prophylactic bilateral oophorectomy for patients at high risk of genetically carried ovarian cancer is important. The use of preadmission assessment is vital to allow the anesthetist to have access to the patient several weeks prior to the operation. The patient’s physical state can be optimized before surgery.

The approach to the disease can be modiﬁﬁed in several ways. The use of better imaging allows the surgeon to be fully aware of the extent of the disease. This may lead to anticipation of and preparation for bowel surgery by both the surgeon and the patient. It may modify the need to operate, as, if more extensive disease is discovered on imaging, we may consider radiotherapy for cervical cancer or neoadjuvant chemotherapy for patients with extensive ovarian cancer. The use of the “risk-of-malignancy index” [12] has been validated as a method to refer cases of ovarian cancer to a center where there is a survival advantage for the patient. We use a cutoff of 200 for the risk-ofmalignancy index and have found it to be very effective. Neoadjuvant chemotherapy may separate out those patients who are chemotherapeutically resistant, and therefore we operate only on those patients who have chemosensitive disease. This again allows for the patient’s condition to be optimized. With the effect of chemotherapy, the ascites disappears and the cachexia often improves. We have active input from dieticians, and patients who are having

2. Complications in Gynecological Oncology

difﬁﬁculties with nutrition are given early support, which may include parenteral nutrition for some.

Not operating is perhaps the best way of reducing operative complications. We screen our patients with postmenopausal bleeding with transvaginal ultrasound. Those patients with thin regular endometrium do not undergo any further investigation. This population amounts to more than 40% of the patient group, and we avoid the risk of operative intervention (relating to outpatient hysteroscopy) for these patients. The likelihood of a missed cancer is very small <<1%.>

The value of the multidisciplinary meeting cannot be overemphasized in the management of reducing complications. An important role in the meeting is that of the specialist pathologist, who provides information leading to either more or less extensive surgery. As well as informing the team about the surgery, the pathological opinion may advise with respect to the need for adjuvant therapy or observation alone without further therapy.

Laparoscopic surgery has not been used widely by oncology centers in the United Kingdom. Our experience is that for endometrial and cervical cancer, there are quite considerable beneﬁﬁts for minimal-access techniques relating to diagnosis and recovery with no adverse effects.

Repair of the midline abdominal incision should use a mass-closure technique with a long-lasting absorbable or nonabsorbable looped suture. Less pain is associated with a long-lasting absorbable suture. Repair of incisional hernia is best achieved with mesh [14].

Having the right surgeon for the operation is very important. The success of the operation is better in centers with a higher frequency of procedure. Surgery in this setting allows the utilization of a surgeon whose is appropriately trained, another factor leading to better outcomes. Junor et al. [15] demonstrated that an operation for ovarian cancer performed by a gynecological oncologist was associated with a 25% better outcome for advanced disease

than an operation performed by the generalist; this translates into a signiﬁﬁcant survival advantage. This ﬁﬁnding is in addition to the patient being managed by the multidisciplinary team and receiving the appropriate chemotherapy.

The use of psychosexual support usually via a specialist nurse who has access to additional expertise is very helpful in alleviating patients’ psychological distress.

Return to theater is a problem that occurs but is difﬁﬁcult to quantify. Early return to theater for an appropriate reason can be life saving. It is essential, therefore, that the postoperative care for the patient is of high quality.

In the West Anglia Cancer Network, we are using videoconferencing, which allows for the interaction of the local unit–level team with the specialist multidisciplinary team at the center. This leads to better discussion and management for patients with cancer and precancer without requiring that patients or clinicians travel to the center.

Conclusion

Gynecological cancer surgery is associated with complications, some of which are avoidable by selecting the correct operation, surgeon, and hospital for the procedure. Other complications may be reduced by optimizing the patient’s condition before surgery and managing the patient in specialist units.

Prevention of Infection Following Gynecological Surgery

2009-03-07T03:10:00.000-08:00

Definition of Infection

Terms such as inﬂﬂammation, contamination, infection, sepsis, and febrile morbidity may mean different things to different clinicians. It is important, therefore, that in audits of surgical outcomes, reports of research ﬁﬁndings, and comparisons of studies, terminology is deﬁﬁned; an example of this process is given in Table 1.1. The deﬁﬁnitions of various systemic inﬂﬂ ammatory responses and their associated clinical ﬁﬁndings and laboratory test results are shown in Table 1.2.

Pathogenesis

The vagina contains more microorganisms than any other site in the body except the bowel. Uterine manipulation through the vagina, e.g., surgical termination of pregnancy (TOP), or operations that open the vagina, e.g., hysterectomy, will result in contamination of normally sterile sites by bacteria that are normally resident in the vagina. Whether these organisms become established and cause infection and inﬂﬂammation depends on a mixture of surgical and host-related factors, including low socioeconomic status, poor nutrition, smoking, or preexisting medical conditions, such as impaired immunocompetence. These risk factors may be interrelated, e.g., diabetes, obesity, increased blood loss, duration of surgery, and prolonged hospital stay, and many of the measures that can be taken to reduce the rate of postoperative infectious morbidity focus on reducing the impact of these risk factors. The risk of postoperative infection also depends on the virulence and size of the bacterial inoculum. Normal vaginal ﬂﬂora is composed mainly of organisms of low virulence, dominated by lactobacilli species, which, by producing lactic acid from glycogen in vaginal secretions, render the pH of the vagina very acid (<4.5), in which milieu the growth of other potentially pathogenic organisms is suppressed.

At this low-acid pH, lactobacilli are particularly efﬁﬁcient at producing H2O2, which is toxic to bacteria. Under conditions where there is an increase in the

Table 1.1. Definition of Infection—Terminology
Definition
Inflammation	Localized protective response elicited by injury or tissue damage
Contamination	Pathogenic microorganism(s) in normally sterile tissue without an
	inflammatory response
Infection	Pathogenic microorganism(s) in normally sterile tissue with a local
	inflammatory response
Sepsis	Infection with a local and systemic inflammatory response
Febrile morbidity	Temperature of >38.0°C on 2 occasions at least 6 hours apart,
	excluding the first 24 hours after the procedure

Source: Adapted from and reproduced with kind permission from Tamussino [1].

alkalinity of the vagina (bleeding, semen, douching) or a change in the delicate vaginal ecosystem (few or poor-quality lactobacilli, antibiotics, changes in endocrine status, or phage virus parasitization of lactobacilli), much less H2O2 is produced. This results in a 1000-fold increase in other organisms, particularly anaerobes that produce keto acids such as succinate. Succinate blunts the chemotactic response of neutrophils and reduces their killing ability. This

Table 1.2. Definitions of Systemic Inflammatory Responses
Clinical Findings, Laboratory
Definition		Tests
Systemic	Signs and symptoms of	Fever, tachypnea, tachycardia,
inflammatory	disseminated infection or	leukocytosis, or leukopenia
response	toxins
Sepsis	Infection with a local and	Tachypnea (>20 breaths/min)
	systemic inflammatory	Tachycardia (>90 bpm)
	response	Hyperthermia or hypothermia
		(>38.4°C or <35.6°c)>
Severe sepsis	Sepsis plus evidence of organ	Metabolic acidosis, acute
	dysfunction	encephalopathy, oliguria,
		hypoxemia, disseminated
		intravascular coagulation,
		hypotension
Septic shock	Infection with an	Hypotension (<90>
	overwhelming systemic	40 mm Hg below baseline)
	inflammatory response
	leading to shock
Sepsis syndrome or	Sepsis plus evidence of altered	Hypoxia, increased plasma
multiple-organ	organ perfusion	lactate, altered mental state,
syndrome		oliguria

Source: Reproduced with kind permission from Tamussino [1].
1. Prevention of Infection Following Gynecological Surgery

results in a synergistic increase in other organisms such as Mobiluncus spp and more anaerobes. The result is a polymicrobial imbalance of large numbers of potentially pathogenic organisms, yet no cellular inﬂﬂammatory response. This condition is called bacterial vaginosis (BV) [2]. As a result, the causative organisms of postoperative infectious morbidity are rarely unimicrobial or exogenous organisms and are more likely to be polymicrobial and endogenous organisms, such as the polymicrobial condition of BV or BV-related organisms, e.g., anaerobes, Mobiluncus, mycoplasmas, and ureaplasmas.

In 2001, the Clinical Effectiveness Group of the Association for Genitourinary Medicine and the Medical Society for the Study of Venereal Diseases produced national guidelines for the management of BV. They listed the complications associated with BV as postabortal sepsis, post-hysterectomy vaginal cuff cellulitis, and abscess post–vaginal hysterectomy. They concluded (level of evidence A) that treatment was indicated for symptomatic women, some pregnant women, and women undergoing some surgical procedures. Most of the evidence pertaining to the use of antibiotics in women undergoing surgery relates to hysterectomy and surgical TOP as an example of transvaginal manipulation of the uterus.

Prophylactic Antibiotics for Hysterectomy

Vaginal Hysterectomy

Hirsch [3] reviewed those studies in which antibiotics were used prophylactically in women undergoing vaginal hysterectomy. As early as 1985, Hirsch was able to ﬁﬁnd 48 studies of 5524 patients, of whom 3037 had been treated and 2487 were used as controls. Febrile morbidity occurred in 444 (15%) of 3037 women who received antibiotics compared to 988 (40%) of 2487 women who did not receive antibiotics (relative risk [RR] = 0.37; 95% conﬁﬁdence interval [CI] = 0.33–0.41; P < 0.01). Similarly, pelvic infections occurred in 105 (5%) of 2099 women who received antibiotics compared to 354 (25%) of 1391 women who did not receive antibiotics (RR = 0.2; CI = 0.16–0.24; P < 0.01).

Abdominal Hysterectomy

As part of the same review [3], Hirsch reviewed those studies in which antibiotics were used prophylactically in women undergoing abdominal hysterectomy. Hirsch found 30 studies involving 3752 patients, of whom 2165 had been treated and 1587 were used as controls. Febrile morbidity occurred in 348 (16%) of 2165 women who received antibiotics compared to 444 (28%) of 1587 women who did not receive antibiotics (RR = 0.57; CI = 0.51–0.65; P < 0.01). Pelvic infection occurred in 57 (5%) of 1196 women who received antibiotics compared to 114 (10%) of 1144 women who did not receive antibiotics (RR = 0.48; CI = 0.35–0.65; P < 0.001). The nature of the abdominal hysterectomy procedure provided a third outcome category—wound infection—for analysis. In this category, 45 (3%) of 1434 women who received antibiotics developed a wound infection compared to 98 (8%) of 1194 women who did not receive antibiotics (RR = 0.38; CI = 0.27–0.54; P < 0.01).

Vaginal Versus Abdominal Hysterectomy

Around the time of the Hirsch review [3], 2 studies [4,5] reported on postoperative complications of vaginal versus abdominal hysterectomy. Shapiro et al. [4] found that a higher incidence of infection at the operation site was associated with increased duration of the procedure, lack of antibiotic prophylaxis, younger age, and an abdominal approach. Correcting for these associations, there was no predictive value of the following: obesity, preoperative functional and anatomical diagnosis, postoperative anatomical and pathological diagnosis, estimated blood loss, menopausal status, or surgeon who performed the procedure. Dicker et al. [5] studied 1851 women from 9 institutions. They found that vaginal hysterectomy when compared to abdominal hysterectomy was associated with signiﬁﬁcantly fewer complications but more unintended surgical procedures. Vaginal hysterectomy was associated with less febrile morbidity, less bleeding requiring transfusion, and less hospitalization and convalescence. Bearing in mind the results of these studies [4,5] and the review by Hirsch [3], in which there were more studies (48 versus 30) and more patients (5524 versus 3752) in which prophylactic antibiotics were used for vaginal hysterectomy compared to abdominal hysterectomy, it seems likely that up to 1985, antibiotics were used preferentially for vaginal hysterectomy compared to abdominal hysterectomy, though the logic of this choice is unclear. This is emphasized by the conclusion of Dicker et al. [5], who claimed that while vaginal hysterectomy with antibiotics had a better outcome than abdominal hysterectomy, the differences were probably attributable to the prevalence and efﬁﬁcacy of antibiotic usage in vaginal hysterectomy.

Bacterial Vaginosis and Post-hysterectomy Infectious Morbidity

Two studies [6,7], in neither of which antibiotic prophylaxis was used, highlighted the association between BV and post-hysterectomy vaginal cuff cellulitis. Soper et al. [6] found that 11 (34%) of 32 women with BV developed post-hysterectomy vaginal cuff cellulitis compared to only 11 (11%) of 102 of women with normal ﬂﬂora (RR = 3.2; CI = 1.5–6.7; P < 0.005). Larsson et al. [7] found that 7 (35%) of 20 women with BV developed post-hysterectomy vaginal cuff infection compared to 4 (8%) of 50 with normal ﬂﬂora (R = 4.4; CI = 1.4– 13.3; P < 0.01).

1. Prevention of Infection Following Gynecological Surgery

Choice of Antibiotics

With the important association of BV and BV-related organisms and the development of post-hysterectomy infectious morbidity, it is important that the antibiotics used prophylactically are active against those organisms, particularly anaerobes. In a metaanalysis, Mittendorf et al. [8] identiﬁﬁed 25 randomized controlled trials of antibiotic prophylaxis that used vigorous protocols. They performed metaanalyses and cumulative metaanalyses for all the trials. Separate metaanalyses were performed for cefazolin, metronidazole, and tinidazole. Overall, 21% (373/1768) of patients who did not receive antibiotic prophylaxis had serious infection after abdominal hysterectomy. In comparison, of women who received any antibiotics, only 9% (166/1836) had serious postoperative infections (P = 0.00001). Among those who received cefazolin, metronidazole, or tinidazole, 11.4% (70/615; P = 0.00021), 6.3% (17/269; P = 0.015), and 5% (5/101; P = 0.034), respectively, had serious postoperative morbidity. The metaanalyses for individual studies and a cumulative metaanalysis are shown in Figure 1.1. Mittendorf et al. concluded that randomized controlled trials of antibiotic prophylaxis in abdominal hysterectomy that used controls who received no treatment are no longer justiﬁﬁed. Moreover, they concluded, if the results of the various studies had been pooled at an earlier date, the inappropriateness of controls who received no treatment would have been discovered in 1980 for cefazolin, in 1984 for metronidazole, and in 1986 for tinidazole.

The Swedish National Study of Infection after Hysterectomy (1996), which took place before publication of the Mittendorf metaanalysis, involved 1060 women from 42 centers, yet included only 236 women (22%) who were given preoperative or postoperative antibiotics [9]. Not surprisingly, the postoperative infection rate was high, at 23%, 9.4% of whom had an infection that was situated either in the wound, in the vaginal cuff, or deep in the pelvis. Thirteen percent had a urinary tract infection (UTI), and 4% had infections distant from the site. Only 50% of the wound, cuff, and deep-pelvic infections were detected before discharge from the hospital. An increased risk of postoperative infection was associated with Wertheims-Meigs hysterectomy (21.4%; RR = 3.0; P <> 1000 mL (15%; RR = 2.4; P < rr =" 2.3;"> 0.05). Admitting that the publication of Mittendorf et al. (1993) [8] had not been drawn to their attention until after preparation of their manuscript, Henriksson et al. (1998) [10] reported that 500 mg of metronidazole administered intravenously to 134 women immediately before total abdominal hysterectomy resulted in a signiﬁﬁcantly lower erythrocyte sedimentation rate on day 6 (50 mm/hr vs 56 mm/hr, P < 0.05), rate of infection (9% vs 17%; P < 0.04), and duration of postoperative hospitalization (7.9 vs 8.8 days; P < 0.02).

1. Prevention of Infection Following Gynecological Surgery

Prevention of Infection Associated with Termination of Pregnancy

Following an unpublished pilot study in Swansea, Wales, in women presenting for TOP, in which the rate of pelvic infection was higher than expected, a larger, more formal study was performed. The study recruited 400 women attending for termination of pregnancy. One hundred twelve women (28%) had BV, 95 (24%) had candida, 3 (0.75%) had Trichomonas, and 1 (0.25%) had gonorrhea. Of 32 women (8%) with chlamydia, 63% developed postabortal pelvic infection, requiring 7 to be readmitted to the hospital. As a result, the authors recommended that, since the estimated cost of hospital admission due to chlamydia was twice the estimated cost of screening for and treating chlamydia, screening for chlamydia was essential, and prophylactic antibiotics should cover both chlamydia and BV [11].

The incidence of postabortal sepsis (PAS) is estimated to be between 4% and 12%. Those women with BV have a 3-fold increased risk of PAS compared to women with Lactobacillus spp–dominated ﬂﬂora [12]. Prophylactic metronidazole reduces PAS by 66% [13,14]. In a randomized, double-blind, placebo-controlled trial of 231 women attending for TOP who were given either 500 mg of metronidazole or placebo for 10 days starting the week preoperatively, the incidence of PAS was 3.8% in the metronidazole group compared with 12.2% in the placebo group (P < style="font-weight: bold;">Infections Postoperative Hysteroscopy

While accepting the recommendations and guidelines from national bodies, clinical effectiveness groups, professional bodies, RCOG study groups, and expert advisory groups concerning the use of antibiotic prophylaxis to prevent infection when uterine instrumentation is involved, a recent report of 1952 operative hysteroscopies from Marseille, France, recorded a remarkably low incidence of postoperative infection despite the fact that no antibiotic prophylaxis was used. Following 782 resections of leiomyomata, 422 endo metrial polypectomies, and 90 uterine septa resections, together with 623 endometrectomies and 199 lyses of intrauterine synechiae, the incidence of endometritis and UTI was extremely low at 18 (0.9%) of 1952 and 12 (0.6%) of 1952, respectively [20].

Conclusion

On July 3, 1909, at the age of 47, Herman Pfannenstiel (1862–1909), the Berlin gynecologist who gave his name to the low transverse incision so commonly used in obstetrics and gynecology, died of septicemia 1 week after a needle-stick injury to his left middle ﬁﬁnger, sustained while operating on a patient with a tubo-ovarian abscess. With the introduction of antibiotics, postoperative infections are no longer the danger they were for patients or their surgeons but are still common, potentially life threatening, and a drain on health care. The following bullet points represent the evidence available for the prevention of infection following gynecological surgery.

Prophylactic antibiotics signiﬁﬁcantly reduce infectious morbidity following hysterectomy and termination of pregnancy.
Vaginal hysterectomy is associated with less infectious morbidity than total abdominal hysterectomy, but all hysterectomies should have antibiotic prophylaxis.
Consensus guidelines also recommend antibiotic prophylaxis for other procedures that involve uterine instrumentation.
Prophylactic antibiotics for TOP are as good as screening and treatment and probably more cost-effective. The possible exception to this rule is among women under the age of 20 years in whom screen

1. Prevention of Infection Following Gynecological Surgery

ing for sexually transmitted infection such as Chlamydia trachoma-tis, gonococcus, and Trichomonas is more likely to result in positive cultures, with the added advantage of genito-urinary medicine (GUM) referral and contact tracing.

Prophylactic antibiotics for TOP should cover both chlamydia and BV (e.g., doxycycline 200 mg daily plus metronidazole 1 g per rectum twice daily or 400 mg three times daily, or erythromycin 500 mg four times daily and clindamycin 300 mg twice daily).
Antibiotic prophylaxis for hysterectomy should be broad spectrum as well as antianaerobe to cover wound infection and UTI as well as cuff cellulitis and deep-pelvic infection (e.g., metronidazole 1 g per rectum before surgery plus 750 mg cefuroxime IV with induction of anesthesia or 1.2 g of co-amoxiclav with the induction of anesthesia).
With the strength of evidence available to show the beneﬁﬁts of antibiotic prophylaxis for hysterectomy and TOP, particularly with respect to covering both chlamydia and BV, together with many other sources of national clinical guidelines and recommendations from government and national expert advisory groups, failure to follow the advice would leave clinicians open to medical litigation.

THE EXTERNAL GENITALIA

2008-08-16T06:57:00.000-07:00

Undifferentiated Stage
The external genitalia begin to form early in the embryonic period, shortly after development of the cloaca. The progenitory tissues of the genitalia are common to both sexes, and the early stage of development is virtually the same in females and males. Although differentiation of the genitalia can begin around the onset of the fetal period if testicular differentiation is initiated, definitive genital sex is usually not clearly apparent until the 12th week. Formation of external genitalia in the male involves the influence of androgen on the interaction of subepidermal mesoderm with the inferior parts of the endodermal urogenital sinus. In the female, this androgenic influence is absent.
The external genitalia form within the initially compact area bounded by the umbilical cord (anteriorly), the developing limb buds (laterally), the embryonic tail (posteriorly), and the cloacal membrane (centrally). Two of the primordia for the genitalia first appear bilaterally adjacent to the cloacal membrane (a medial pair of cloacal folds and a lateral pair of genital [labioscrotal] swellings). The cloacal folds are longitudinal proliferations of caudal mesenchyme located between the ectodermal epidermis and the underlying endoderm of the phallic part of the urogenital sinus. Proliferation and bilateral anterior fusion of these folds create the genital tubercle, which protrudes near the anterior edge of the cloacal membrane by the sixth week (Fig 4–24, Fig 4–25 and Fig 4–26). Extension of the tubercle forms the phallus, which at this stage is the same size in both sexes.
By the seventh week, the urorectal septum subdivides the bilayered (ectoderm and endoderm) cloacal membrane into the urogenital membrane (anteriorly) and the anal membrane (posteriorly). The area of fusion of the urorectal septum and the cloacal membrane becomes the primitive perineum, or perineal body. With formation of the perineum, the cloacal folds are divided transversely as urogenital folds adjacent to the urogenital membrane and anal folds around the anal membrane. As the mesoderm within the urogenital folds thickens and elongates between the perineum and the phallus, the urogenital membrane sinks deeper into the fissure between the folds. Within a week, this membrane ruptures, forming the urogenital orifice and, thus, opening the urogenital sinus to the exterior. Similar thickening of the anal folds creates a deep anal pit, in which the anal membrane breaks down to establish the anal orifice of the anal canal (Fig 4–24 and Fig 4–25).
Subsequent masculinization or feminization of the external genitalia is a consequence of the respective presence or absence of androgen and the androgenic sensitivity or insensitivity of the tissues. The significance of both of these factors (availability of hormone and sensitivity of target tissue) is exemplified by the rare condition (about 1 in 50,000 “females”) of testicular feminization, wherein testes are present (usually ectopic) and produce testosterone and anti-müllerian hormone. The anti-müllerian hormone suppresses formation of the uterus and uterine tubes (from the paramesonephric ducts), whereas testosterone supports male differentiation of the mesonephric ducts to form the epididymis and ductus deferens. The anomalous feminization of the external genitalia is considered to be due to androgenic insensitivity of the precursor tissues consequent to an abnormal androgen receptor or postreceptor mechanism set by genetic inheritance.

Male
Early masculinization of the undifferentiated or indifferent genitalia takes place during the first 3 weeks of the fetal period (weeks 9–12) and is caused by androgenic stimulation. The phallus and urogenital folds gradually elongate to initiate development of the penis. The subjacent endodermal lining of the inferior part (phallic) of the urogenital sinus extends anteriorly along with the urogenital folds, creating an endodermal plate, the urethral plate. The plate deepens into a groove, the urethral groove, as the urogenital folds (now called urethral folds) thicken on each side of the plate. The urethral groove extends into the ventral aspect of the developing penis, and the bilateral urethral folds slowly fuse in a posterior to anterior direction over the urethral groove to form the spongy (penile) urethra, thereby closing the urogenital orifice (Fig 4–17 and Fig 4–24). The line of fusion becomes the penile raphe on the ventral surface of the penis.
As closure of the urethral folds approaches the glans, the external urethral opening on this surface is eliminated. Concurrently, an ectodermal glandular plate invaginates the tip of the penis. Canalization of the plate forms the distal end of the penile urethra, the glandular urethra. Thus, the external urethral meatus becomes located at the tip of the glans when closure of the urethral folds is completed (Fig 4–24). The prepuce is formed slightly later by a circular invagination of ectoderm at the tip of the glans penis. This cylindric ectodermal plate then cleaves to leave a double-layered fold of skin extending over the glans.
While the cloacal folds and phallic urogenital sinus were differentiating into the penis and the urethra, the genital (labioscrotal) swellings of the undifferentiated stage were enlarging lateral to the cloacal folds. Medial growth and fusion of the scrotal swellings to form the scrotum and scrotal raphe around the 12th week virtually complete the differentiation of the male external genitalia (Fig 4–24 and Fig 4–26).

Female
A. DEVELOPMENT OF EXTERNAL GENITALIA

Feminization of the external genitalia proceeds in the absence of androgenic stimulation (or nonresponsiveness of the tissue). The 2 primary distinctions in the general process of feminization versus masculinization are (1) the lack of continued growth of the phallus and (2) the near absence of fusion of the urogenital folds and the labioscrotal swellings. Female derivatives of the indifferent sexual primordia for the external genitalia are virtually homologous counterparts of the male derivatives. Formation of the female genitalia is schematically presented in Fig 4–25.
The growth of the phallus slows relative to that of the urogenital folds and labioscrotal swellings and becomes the diminutive clitoris. The anterior extreme of the urogenital folds fuses superior and inferior to the clitoris, forming the prepuce and frenulum of the clitoris, respectively. The midportions of these folds do not fuse but give rise to the labia minora. Lack of closure of the folds leaves the urogenital orifice patent and results in formation of the vestibule of the vagina from the inferior portion of the pelvic part and the phallic part of the urogenital sinus at about the fifth month (Fig 4–25). Derivatives of the vesical part of the sinus (the urethra) and the superior portion of the pelvic part of the sinus (vagina and greater vestibular glands) then open separately into the vestibule. The frenulum of the labia minora is formed by fusion of the posterior ends of the urogenital folds. The mesoderm of the labioscrotal swellings proliferates beneath the ectoderm and remains virtually unfused to create the labia majora lateral to the labia minora. The swellings blend together anteriorly to form the anterior labial commissure and the tissue of the mons pubis, while the swellings posteriorly less clearly define a posterior labial commissure. The distal fibers of the round ligament of the uterus project into the tissue of the labia majora.

B. ANOMALIES OF THE LABIA MINORA

In otherwise normal females, 2 somewhat common anomalies occur—labial fusion and labial hypertrophy. True labial fusion as an early developmental defect in the normally unfused midportions of the urogenital folds is purportedly less frequent than “fusion” due to inflammatory-type reactions. Labial hypertrophy can be unilateral or bilateral and may require surgical correction in extreme cases.

C. ANOMALIES OF THE LABIA MAJORA

The labia majora are derived from the bilateral genital (labioscrotal) swellings, which appear early in the embryonic period and remain unfused centrally during subsequent sex differentiation in the fetal period. Anomalous conditions include hypoplastic and hypertrophic labia as well as different gradations of fusion of the labia majora. Abnormal fusion (masculinization) of labioscrotal swellings in genetic females is most commonly associated with ambiguous genitalia of female pseudohermaphroditism consequent to congenital adrenal hyperplasia (adrenogenital syndrome). Over 90% of females with congenital adrenal hyperplasia have a steroid 21-hydroxylase deficiency (autosomal recessive), resulting in excess adrenal androgen production. This enzyme deficiency has been reported to be “the most common cause of ambiguous genitalia in genetic females.” Associated anomalies include clitoral hypertrophy and persistent urogenital sinus. Formation of a penile urethra is extremely rare.

D. ANOMALIES OF THE CLITORIS

Clitoral agenesis is extremely rare and is due to lack of formation of the genital tubercle during the sixth week. Absence of the clitoris could also result from atresia of the genital tubercle. The tubercle forms by fusion of the anterior segments of the cloacal folds. Very rarely, these anterior segments fail to fuse, and a bifid clitoris forms. This anomaly also occurs when unification of the anterior parts of the folds is restricted by exstrophy of the cloaca or bladder. Duplication of the genital tubercle with consequent formation of a double clitoris is equally rare. Clitoral hypertrophy alone is not common but may be associated with various intersex disorders.

E. ANOMALIES OF THE PERINEUM

The primitive perineum originates at the area of contact of the mesodermal urorectal septum and the endodermal dorsal surface of the cloacal membrane (at 7 weeks). During normal differentiation of the external genitalia in the fetal period, the primitive perineum maintains the separation of the urogenital folds and ruptured urogenital membrane from the anal folds and ruptured anal membrane, and later develops the perineal body. Malformations of the perineum are rare and usually associated with malformations of cloacal or anorectal development consequent to abnormal development of the urorectal septum. Imperforate anus has an incidence of about 0.02%. The simplest form (rare) is a thin membrane over the anal canal (the anal membrane failed to rupture at the end of the embryonic period). Anal stenosis can arise by posterior deviation of the urorectal septum as the septum approaches the cloacal membrane, causing the anal membrane to be smaller (with a relatively increased anogenital distance through the perineum). Anal agenesis with a fistula detected as an ectopic anus is considered to be a urorectal septal defect. The incidence of agenesis with a fistula is only slightly less than that without a fistula. In females, the fistula commonly may be located in the perineum (perineal fistula) or may open into the posterior aspect of the vestibule of the vagina (anovestibular fistula; see Cloacal Dysgenesis).

* Embryonic or fetal ages given in this chapter are relative to the time of fertilization and should be considered estimates rather than absolutes.

DIFFERENTIATION OF THE UROGENITAL SINUS

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Until differentiation of the genital ducts begins, the urogenital sinus appears similar in both sexes during the middle and late embryonic period. For purposes of describing the origin of sinusal derivatives, the sinus can be divided into 3 parts: (1) the vesical part, or the large dilated segment superior to the entrance of the mesonephric ducts; (2) the pelvic part, or the narrowed tubular segment between the level of the mesonephric ducts and the inferior segment; and (3) the phallic part, often referred to as the definitive urogenital sinus (the anteroposteriorly elongated, transversely flattened inferiormost segment) (Fig 4–12). The urogenital membrane temporarily closes the inferior limit of the phallic part. The superior limit of the vesical part becomes delimited by conversion of the once tubular allantois to a thick fibrous cord, the urachus, by about 12 weeks. After differentiation of the vesical part of the sinus to form the epithelium of the urinary bladder, the urachus maintains its continuity between the apex of the bladder and the umbilical cord and is identified postnatally as the median umbilical ligament. Various anomalies of urachal formation can present as urachal fistula, cyst, or sinus, depending on the degree of patency that persists during obliteration of the allantois.
In both sexes, the caudal segments of each mesonephric duct between the urogenital sinus and the level of the ureter of the differentiating metanephric diverticulum (or ureteric bud) become incorporated into the posterocaudal wall of the vesical part (ie, urinary bladder) of the sinus (Fig 4–9 and Fig 4–10). As the dorsal wall of the bladder grows and “absorbs” these caudal segments, the ureters are gradually “drawn” closer to the bladder and eventually open directly and separately into it, dorsolateral to the mesonephric ducts (Fig 4–10 and Fig 4–11). The mesodermal segment of mesonephric duct incorporated into the bladder defines the epithelium of the trigone of the bladder, although this mesodermal epithelium is secondarily replaced by the endodermal epithelium of the sinusal bladder. After formation of the trigone, the remainder of each mesonephric duct (ie, the portion that was cranial to the metanephric diverticulum) is joined to the superior end of the pelvic part of the urogenital sinus. Thereafter, the ducts either degenerate (in females) or undergo differentiation (in males), as already discussed.
The urogenital sinus gives rise to the endodermal epithelium of the urinary bladder, the prostatic and membranous urethra, and most of the spongy (penile) urethra (except the glandular urethra). Outgrowths from its derivatives produce epithelial parts of the prostate and bulbourethral glands (Fig 4–17). The prostatic urethra receives the ejaculatory ducts (derived from the mesonephric ducts) and arises from 2 parts of the urogenital sinus. The portion of this urethral segment superior to the ejaculatory ducts originates from the inferiormost area of the vesical part of the sinus. The lower portion of the prostatic urethra is derived from the pelvic part of the sinus near the entrance of the ducts and including the region of the sinusal tubercle—the latter apparently forming the seminal colliculus. Early in the 12th week, endodermal outgrowths of the prostatic urethra form the prostatic anlage, the prostatic buds, from which the glandular epithelium of the prostate will arise. Differentiation of splanchnic mesoderm contributes other components to the gland (smooth muscle and connective tissue), as is the case also for mesodermal parts of the urinary bladder. The pelvic part of the sinus also gives rise to the epithelium of the membranous urethra, which later yields endodermal buds for the bulbourethral glands. The phallic, or inferior, part of the urogenital sinus proliferates anteriorly as the external genitalia form (during weeks 9–12) and results in incorporation of this phallic part as the endodermal epithelium of the spongy (penile) urethra (the distal glandular urethra is derived from ectoderm; see below).

Female: Urinary Bladder, Urethra, and Vagina
A. DEVELOPMENT
Differentiation of the female sinus is schematically presented in Fig 4–18 and illustrated in Fig 4–12 and Fig 4–19, Fig 4–20 and Fig 4–21. In contrast to sinusal differentiation in the male, the vesical part of the female urogenital sinus forms the epithelium of the urinary bladder and entire urethra. Derivatives of the pelvic part of the sinus include the epithelium of the vagina, the greater vestibular glands, and the hymen. Controversy exists about how the vagina is formed, mainly because of a lack of consensus about the origin and degree of inclusion of its precursory tissues (mesodermal paramesonephric duct, endodermal urogenital sinus, or even mesonephric duct). The most common theory is that 2 endodermal outgrowths, the sinovaginal bulbs, of the dorsal wall of the pelvic part of the urogenital sinus form bilateral to and join with the caudal tip of the uterovaginal primordium (fused paramesonephric ducts) in the area of the sinusal tubercle (Fig 4–19). This cellular mass at the end of the primordium occludes the inferior aspect of the canal, creating an endodermal vaginal plate within the mesodermal wall of the uterovaginal primordium. Eventually, the vaginal segment grows, approaching the vestibule of the vagina. The process of growth has been described either as “down-growth” of the vaginal segment away from the uterine canal and along the urogenital sinus or, more commonly, as “up-growth” of the segment away from the sinus and toward the uterovaginal canal. In either case, the vaginal segment is extended between the paramesonephric-derived cervix and the sinus-derived vestibule (Fig 4–19, Fig 4–20 and Fig 4–21). Near the fifth month, the breakdown of cells centrally in the vaginal plate creates the vaginal lumen, which is delimited peripherally by the remaining cells of the plate as the epithelial lining of the vagina. The solid vaginal fornices become hollow soon after canalization of the vaginal lumen is complete. The upper one-third to four-fifths of the vaginal epithelium has been proposed to arise from the uterovaginal primordium, while the lower two-thirds to one-fifth has been proposed as a contribution from the sinovaginal bulbs.
The fibromuscular wall of the vagina is derived from the uterovaginal primordium. The cavities of the vagina and urogenital sinus are temporarily separated by the thin hymen, which is probably a mixture of tissue derived from the vaginal plate and the remains of the sinusal tubercle. With concurrent differentiation of female external genitalia, inferior closure of the sinus does not occur during the 12th week of development, as it does in the male. Instead, the remainder of the pelvic part and all of the inferior phallic part of the urogenital sinus expand to form the vestibule of the vagina. Presumably, the junctional zone of pigmentation on the labia minora represents the distinction between endodermal derivation from the urogenital sinus (medially) and ectodermal skin (laterally).

B. ANOMALIES OF THE VAGINA
The vagina is derived from interaction between the uterovaginal primordium and the pelvic part of the urogenital sinus (Fig 4–18; see previous section above). The causes of vaginal anomalies are difficult to assess because integration of the uterovaginal primordium and the urogenital sinus in the normal differentiation of the vagina remains a controversial subject. Furthermore, an accurate breakdown of causes of certain anomalous vaginal presentations, as with many anomalies of the external genitalia, would have to include potential moderating factors of endocrine and genetic origin as well.
The incidence of absence of the vagina due to suspected vaginal agenesis is about 0.025%. Agenesis may be due to failure of the uterovaginal primordium to contact the urogenital sinus. The uterus is usually absent (Fig 4–22). Ovarian agenesis is not usually associated with vaginal agenesis. The presence of greater vestibular glands has been reported with presumed vaginal agenesis; their presence emphasizes the complexity of differentiation of the urogenital sinus.
Vaginal atresia, on the other hand, is considered when the lower portion of the vagina consists merely of fibrous tissue while the contiguous superior structures (the uterus, in particular) are well differentiated (perhaps because the primary defect is in the sinusal contribution to the vagina). In müllerian aplasia almost all of the vagina and most of the uterus are absent (Rokitansky-Küster-Hauser syndrome, with a rudimentary uterus of bilateral, solid muscular tissue, was considered virtually the same as this aplasia). Most women with absence of the vagina (and normal external genitalia) are considered to have müllerian aplasia rather than vaginal atresia.
Other somatic anomalies are sometimes associated with müllerian aplasia, suggesting multiple malformation syndrome. Associated vertebral anomalies are much more prevalent than middle ear anomalies, eg, müllerian aplasia associated with Klippel-Feil syndrome (fused cervical vertebrae) is more common than müllerian aplasia associated with Klippel-Feil syndrome plus middle ear anomalies (“conductive deafness”). Winter's syndrome, which is thought to be autosomal recessive, is evidenced by middle ear anomalies (somewhat similar to those in the triad above), renal agenesis or hypoplasia, and vaginal atresia (rather than aplasia of the paramesonephric ducts). Dysgenesis (partial absence) of the vagina and hypoplasia (reduced caliber of the lumen) have also been described.
Transverse vaginal septa (Fig 4–23) are probably not the result of vaginal atresia but rather of incomplete canalization of the vaginal plate or discrete fusion of sinusal and primordial (ductal) derivatives. Alternative explanations are likely since the histologic composition of septa is not consistent. A rare genetic linkage has been demonstrated. A single septum or multiple septa can be present, and the location may vary in upper or lower segments of the lumen. Longitudinal vaginal septa can also occur. A variety of explanations have been advanced, including true duplication of vaginal primordial tissue, anomalous differentiation of the uterovaginal primordium, abnormal variation of the caudal fusion of the müllerian ducts, persistence of vaginal plate epithelium, and anomalous mesodermal proliferation. Septa may be imperforate or perforated. A transverse septum creates the potential for various occlusive manifestations (eg, hydrometrocolpos, hematometra, or hematocolpos, depending on the composition of the trapped fluid). (See Chapter 31.)
Abnormalities of the vagina are often associated with anomalies of the urinary system and the rectum because differentiation of the urogenital sinus is involved in formation of the bladder and urethra as well as the vagina and vestibule. Furthermore, if partitioning of the cloaca into the sinus and anorectal canal is faulty, then associated rectal defects can occur. Compound anomalies may affect the urinary tract or rectum. The urethra may open into the vaginal wall; even a single vesicovaginal cavity has been described. On the other hand, the vagina can open into a persistent urogenital sinus, as in certain forms of female pseudohermaphroditism. Associated rectal abnormalities include vaginorectal fistula, vulvovaginal anus, rectosigmoidal fistula, and vaginosigmoidal cloaca in the absence of the rectum (see also Cloacal Dysgenesis, below).

C. ANOMALIES OF THE HYMEN
The hymen is probably a mixture of tissue derived from remains of the sinusal tubercle and the vaginal plate. Usually, the hymen is patent, or perforate, by puberty, although an imperforate hymen is not rare. The imperforate condition can be a congenital error of lack of central degeneration or a result of inflammatory occlusion after perforation. Obstruction of menstrual flow at puberty may be the first sign (Fig 4–23).

D. CLOACAL DYSGENESIS (INCLUDING PERSISTENCE OF THE UROGENITAL SINUS)
Anomalous partitioning of the cloaca by the abnormal development of the urorectal septum is rare, at least based on reported cases in the literature. As anticipated from a developmental standpoint, the incidence of associated genitourinary anomalies is high. Five types of cloacal or anorectal malformations are summarized in Table 4–3.
Rectocloacal fistula with a persistent cloaca provides a common canal or outlet for the urinary, genital, and intestinal tracts. The distinction between a canal and an outlet is one of depth (deep versus very shallow, respectively) of the persistent lower portion of the cloaca and, thus, the length of the individual urethral and vaginal canals emptying into the cloaca. The inverse relationship between depth (or length) of the cloaca and length of the vaginal and urethral canals is probably a reflection of the time when arrest of formation of the urorectal septum occurs. Although the bladder, the vagina, and the rectum can empty into a common cloaca as just described, other unusual variations of persistent cloaca can also occur.
For example, the vagina and rectum develop, but the urinary bladder does not develop as a separate entity from the cloaca. Instead, the vagina and rectum open separately into a “urinary bladder,” which has ureters entering posterolaterally to the vagina (vaginal orifice is in the “anatomic trigone” of the bladder-like structure). The external orifice from the base of this cloacal “bladder” is a single narrow canal. One explanation for this variant might be that arrest of formation of the urorectal septum occurs much earlier than does the separate development of distal portions of the 3 tracts (urethra, vagina, and anorectum) to a more advanced (but still incomplete) stage before urorectal septal formation ceases. The anomaly is probably rare.
With a rectovaginal fistula, the vestibule may appear anatomically normal but the anus does not appear in the perineum. The defect probably results from anorectal agenesis due to incomplete subdivision of the cloaca (similar agenesis in the male could result in a rectourethral fistula). The development of the anterior aspect of the vagina completes the separation of the urethra from the vagina, so there is not a persistent urogenital sinus. Anorectal agenesis is reputedly the most common type of anorectal malformation, and usually a fistula occurs. Rectovaginal, anovestibular (or rectovestibular; Table 4–3), and anoperineal fistulas account for most anorectal malformations.
In the absence of the anorectal defect (normal anal presentation) but presence of a persistent urogenital sinus with a single external orifice, various irregularities of the urethra and genitalia can appear. The relative positions of urethral and vaginal orifices in the sinus can even change as the child grows. In the discussion of anomalies of the labia majora (see following text), note is made of the association of a persistent urogenital sinus in female pseudohermaphroditism due to congenital adrenal hyperplasia. The vagina opens into the persisting pelvic part of the sinus, which extends with the phallic part of the sinus to the external surface at the urogenital opening. The sinus can be deep and narrow in the neonate, approximating the size of a urethra, or it can be relatively shallow.
Urinary tract disorders associated with persistent urogenital sinus include duplication of the ureters, unilateral ureteral and renal agenesis or atresia, and lack of or abnormal ascent of the kidneys. Variations in the anomalies of derivatives of the urogenital sinus appear to be related in part to the time of arrest of normal differentiation and development of the urogenital sinus, as well as to the impact of other factors associated with abnormal sexual differentiation, such as the variable degrees of response to adrenal androgen in congenital adrenal hyperplasia.

SUBDIVISION OF THE CLOACA & FORMATION OF THE UROGENITAL SINUS

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The endodermally lined urogenital sinus is derived by partitioning of the endodermal cloaca; it is the precursor of the urinary bladder in both sexes and the urinary and genital structures specific to each sex (see Fig 4–1). The cloaca is a pouch-like enlargement of the caudal end of the hindgut and is formed by the process of “folding” of the caudal region of the embryonic disk between 4 and 5 weeks' gestation (see Overview of the First Four Weeks of Development, above; Fig 4–1 and Fig 4–4). During the “tail-fold” process, the posteriorly placed allantois, or allantoic diverticulum of the yolk sac, becomes an anterior extension of the cloaca (Fig 4–4 and Fig 4–9). Soon after the cloaca forms, it receives posterolaterally the caudal ends of the paired mesonephric ducts and hence becomes a junctional cistern for the allantois, the hindgut, and the ducts (Fig 4–7). A cloacal membrane, composed of ectoderm and endoderm, is the caudal limit of the primitive gut and temporarily separates the cloacal cavity from the extraembryonic confines of the amniotic cavity (Fig 4–7 and Fig 4–9).
Between weeks 5 and 7, 3 wedges of splanchnic mesoderm, collectively called the urorectal septum, proliferate in the coronal plane in the caudal region of the embryo to eventually subdivide the cloaca (Fig 4–9, Fig 4–10, Fig 4–11 and Fig 4–12). The superior wedge, called the Tourneux fold, is in the angle between the allantois and the primitive hindgut, and it proliferates caudally into the superior end of the cloaca (Fig 4–9). The other 2 mesodermal wedges, called the Rathke folds, proliferate in the right and left walls of the cloaca. Beginning adjacent to the cloacal membrane, these laterally placed folds grow toward each other and the Tourneux fold. With fusion of the 3 folds creating a urorectal septum, the once single chamber is subdivided into the primitive urogenital sinus (ventrally) and the anorectal canal of the hindgut (dorsally; see Fig 4–10, Fig 4–11 and Fig 4–12). The mesonephric ducts and allantois then open into the sinus. The uterovaginal primordium of the fused paramesonephric ducts will contact the sinusal wall between the mesonephric ducts early in the ninth week of development. Formation of the external genitalia is discussed below. However, it can be noted that the junctional point of fusion of the cloacal membrane and urorectal septum forms the primitive perineum (later differentiation creates the so-called perineal body of tissue) and subdivides the cloacal membrane into the urogenital membrane (anteriorly) and the anal membrane (posteriorly; Fig 4–9, Fig 4–12, Fig 4–14, and Fig 4–24).

THE GENITAL DUCTS
Indifferent (Sexless) Stage
Two pairs of genital ducts are initially present in both sexes: (1) the mesonephric (wolffian) ducts, which give rise to the male ducts and a derivative, the seminal vesicles; and (2) the paramesonephric (müllerian) ducts, which form the oviducts, uterus, and part of the vagina. When the adult structures are described as derivatives of embryonic ducts, this refers to the epithelial lining of the structures. Muscle and connective tissues of the differentiating structures originate from splanchnic mesoderm and mesenchyme adjacent to ducts. Mesonephric ducts are originally the excretory ducts of the mesonephric “kidneys” (see previous text), and they develop early in the embryonic period, about 2 weeks before development of paramesonephric ducts (weeks 6–10). The 2 pairs of genital ducts share a close anatomic relationship in their bilateral course through the urogenital ridge. At their caudal limit, both sets contact the part of the cloaca that is later separated as the urogenital sinus (Fig 4–9, Fig 4–10, and Fig 4–14). Determination of the ductal sex of the embryo (ie, which pair of ducts will continue differentiation rather than undergo regression) is established initially by the gonadal sex and later by the continuing influence of hormones.
Formation of each paramesonephric duct begins early in the sixth week as an invagination of coelomic epithelium in the lateral wall of the cranial end of the urogenital ridge and adjacent to each mesonephric duct (Fig 4–5). The free edges of the invaginated epithelium join to form the duct except at the site of origin, which persists as a funnel-shaped opening, the future ostium of the oviduct. At first, each paramesonephric duct grows caudally through the mesenchyme of the urogenital ridge and laterally parallel to a mesonephric duct. More inferiorly, the paramesonephric duct has a caudomedial course, passing ventral to the mesonephric duct (Fig 4–7). As it follows the ventromedial bend of the caudal portion of the urogenital ridge, the paramesonephric duct then lies medial to the mesonephric duct, and its caudal tip lies in close apposition to its counterpart from the opposite side (Fig 4–14). At approximately the eighth week, the caudal segments of the right and left ducts fuse medially and their lumens coalesce to form a single cavity. This conjoined portion of the Y-shaped paramesonephric ducts becomes the uterovaginal primordium, or canal.
Male: Genital Ducts

A. MESONEPHRIC DUCTS

The mesonephric ducts persist in the male and, under the stimulatory influence of testosterone, differentiate into the internal genital ducts (epididymis, ductus deferens, and ejaculatory ducts). Near the cranial end of the duct, some of the mesonephric tubules (epigenital mesonephric tubules) of the mesonephric kidney persist lateral to the developing testis. These tubules form a connecting link, the ductuli efferentes, between the duct and the rete testis (Fig 4–14). The cranial portion of each duct becomes the convoluted ductus epididymis. The ductus deferens forms when smooth muscle from adjacent splanchnic mesoderm is added to the central segment of the mesonephric duct. The seminal vesicle develops as a lateral bud from each mesonephric duct just distal to the junction of the duct and the urogenital sinus (Fig 4–11). The terminal segment of the duct between the sinus and seminal vesicle forms the ejaculatory duct, which becomes encased by the developing prostate gland early in the 12th week (see Differentiation of the Urogenital Sinus later in chapter). A vestigial remnant of the duct may persist cranially near the head of the epididymis as the appendix epididymis, whereas remnants of mesonephric tubules near the inferior pole of the testis and tail of the epididymis may persist as the paradidymis (Fig 4–14).

B. PARAMESONEPHRIC DUCTS

The paramesonephric ducts begin to undergo morphologic regression centrally (and progress cranially and caudally) about the time they meet the urogenital sinus caudally (approximately the start of the ninth week). Regression is effected by nonsteroidal anti-müllerian hormone produced by the differentiating Sertoli cells slightly before androgen is produced by the Leydig cells (see Testis). Anti-müllerian hormone is produced from the time of early testicular differentiation until birth (ie, not only during the period of regression of the paramesonephric duct). However, ductal sensitivity to anti-müllerian hormone in the male seems to exist for only a short “critical” time preceding the first signs of ductal regression. Vestigial remnants of the cranial end of the ducts may persist as the appendix testis on the superior pole of the testis (Fig 4–14). Caudally, a ductal remnant is considered to be part of the prostatic utricle of the seminal colliculus in the prostatic urethra.

C. RELOCATION OF THE TESTES AND DUCTS

Around weeks 5–6, a bandlike condensation of mesenchymal tissue in the urogenital ridge forms near the caudal end of the mesonephros. Distally, this gubernacular precursor tissue grows into the area of the undifferentiated tissue of the anterior abdominal wall and toward the genital swellings. Proximally, the gubernaculum contacts the mesonephric duct when the mesonephros regresses and the gonad begins to form. By the start of the fetal period, the mesonephric duct begins differentiation and the gubernaculum adheres indirectly to the testis via the duct, which lies in the mesorchium of the testis. The external genitalia differentiate over the seventh to about the 19th week. By the 12th week, the testis is near the deep inguinal ring, and the gubernaculum is virtually at the inferior pole of the testis, proximally, and in the mesenchyme of the scrotal swellings, distally.
Although the testis in early development is near the last thoracic segment, it is still close to the area of the developing deep inguinal ring. With rapid growth of the lumbar region and “ascent” of the metanephric kidney, the testis remains relatively immobilized by the gubernaculum, although there is the appearance of a lengthy transabdominal “descent” from an upper abdominal position. The testis descends through the inguinal canal around the 28th week and into the scrotum about the 32nd week. Testicular blood vessels form when the testis is located on the dorsal body wall and retain their origin during the transabdominal and pelvic descent of the testis. The mesonephric duct follows the descent of the testis and hence passes anterior to the ureter, which follows the retroperitoneal ascent of the kidney (Fig 4–14).
Female: Uterus and Uterine Tubes

Virtually all portions of these paired ducts degenerate in the female embryo, with the exception of the most caudal segment between the ureteric bud and the cloaca, which is later incorporated into the posterior wall of the urogenital sinus (Fig 4–9 and Fig 4–10) as the trigone of the urinary bladder. Regression begins just after gonadal sex differentiation and is finished near the onset of the third trimester. Cystlike or tubular vestiges of mesonephric duct (Fig 4–15) may persist to variable degrees parallel with the vagina and uterus (Gartner's cysts). Other mesonephric remnants of the duct or tubules may persist in the broad ligament (epoophoron).

B. PARAMESONEPHRIC DUCTS

Differentiation of müllerian ducts in female embryos produces the uterine tubes, uterus, and probably the fibromuscular wall of the vagina. In contrast to the ductal/gonadal relationship in the male, ductal differentiation in the female does not require the presence of ovaries. Formation of the bilateral paramesonephric ducts during the second half of the embryonic period has been described (see Indifferent Stage, in previous text). By the onset of the fetal period, the 2 ducts are joined caudally in the midline, and the fused segment of the new Y-shaped ductal structure is the uterovaginal primordium (Fig 4–12). The nonfused cranial part of each paramesonephric duct gives rise to the uterine tubes (oviducts), and the distal end of this segment remains open and will form the ostium of the oviduct.
Early in the ninth week, the uterovaginal primordium contacts medianly the dorsal wall of the urogenital sinus. This places the primordium at a median position between the bilateral openings of the mesonephric ducts, which joined the dorsal wall during the fifth week before subdivision of the urogenital sinus from the cloaca occurred (Fig 4–12 and Fig 4–13). A ventral protrusion of the dorsal wall of the urogenital sinus forms at the area of contact of the uterovaginal primordium with the wall and between the openings of the mesonephric ducts. In reference to its location, this protrusion is called the sinusal tubercle (sinus tubercle, paramesonephric tubercle, müllerian tubercle). This tubercle may consist of several types of epithelia derived from the different ducts as well as from the wall of the sinus.
Shortly after the sinusal tubercle forms, midline fusion of the middle and caudal portions of the paramesonephric ducts is complete, and the vertical septum (apposed walls of the fused ducts) within the newly established uterovaginal primordium degenerates, creating a single cavity or canal (Fig 4–19). The solid tip of this primordium continues to grow caudally, while a mesenchymal thickening gradually surrounds the cervical region of the uterovaginal primordium. The primordium gives rise to the fundus, body, and isthmus of the uterus, specifically the endometrial epithelium and glands of the uterus. The endometrial stroma and smooth muscle of the myometrium are derived from adjacent splanchnic mesenchyme. The epithelium of the cervix forms from the lower aspect of the primordium. Development of the various components of the uterus covers the 3 trimesters of gestation. The basic structure is generated during the latter part of the first trimester. The initial formation of glands and muscular layer occurs near midgestation, whereas mucinous cells in the cervix appear during the third trimester.
The formation of the vagina is discussed below with differentiation of the urogenital sinus, even though it has not been resolved whether the vaginal epithelium is a sinusal or paramesonephric derivative (or both). The fibromuscular wall of the vagina is generally considered to be derived from the uterovaginal primordium (Fig 4–18).

C. RELOCATION OF THE OVARIES AND FORMATION OF LIGAMENTS
Transabdominal “descent” of the ovary, unlike that of the testis, is restricted to a relatively short distance, presumably (at least partly) because of attachment of the gubernaculum to the paramesonephric duct. Hence, relocation of the ovary appears to involve both (1) a passive rotatory movement of the ovary as its mesentery is drawn by the twist of the developing ductal mesenteries and (2) extensive growth of the lumbosacral region of the fetus. The ovarian vessels (like the testicular vessels) originate or drain near the point of development of the gonad, the arteries from the aorta just inferior to the renal arteries and the veins to the left renal vein or to the vena cava from the right gonad.
Initial positioning of the ovary on the anteromedial aspect of the urogenital ridge is depicted in Fig 4–14, as is the relationship of the paramesonephric duct lateral to the degenerating mesonephros, the ovary, and the urogenital mesentery. The urogenital mesentery between the ridge and the dorsal body wall represents the first mesenteric support for structures developing in the ridge.
Alterations within the urogenital ridge eventually result in formation of contiguous double-layered mesenteries supporting the ovary and segments of the paramesonephric ducts. Enlargement of the ovary and degeneration of the adjacent mesonephric tissue bring previously separated layers of coelomic mesothelium into near apposition, establishing the mesentery of the ovary, the mesovarium. Likewise, mesonephric degeneration along the region of differentiation of the unfused cranial segment of the paramesonephric ducts establishes the mesosalpinx. Caudally, growth and fusion ventromedially of these bilateral ducts “sweep” the once medially attached mesenteries of the ducts toward the midline. These bilateral mesenteries merge over the fused uterovaginal primordium and extend laterally to the pelvic wall to form a continuous double-layered “drape,” the mesometrium of the broad ligament, between the upper portion of the primordium and the posterolateral body wall. This central expanse of mesentery creates the rectouterine and vesicouterine pouches. The midline caudal fusion of the ducts also alters the previous longitudinal orientation of the upper free segments of the ducts (the oviducts) to a near transverse orientation. During this alteration, the attached mesovarium is drawn from a medial relationship into a posterior relationship with the paramesonephric mesentery of the mesosalpinx and the mesometrium.
The suspensory ligament of the ovary, through which the ovarian vessels, nerves, and lymphatics traverse, forms when cranial degeneration of the mesonephric tissue and regression of the urogenital ridge adjacent to the ovary reduce these tissues to a peritoneal fold.
The round ligament of the uterus and the proper ovarian ligament are both derivatives of the gubernaculum, which originates as a mesenchymal condensation at the caudal end of the mesonephros and extends over the initially short distance to the anterior abdominal wall (see Relocation of the Testes and Ducts in previous text). As the gonad enlarges and the mesonephric tissue degenerates, the cranial attachment of the gubernaculum appears to “shift” to the inferior aspect of the ovary. Distally, growth of the fibrous gubernaculum continues into the inguinal region. However, the midportion of the gubernaculum becomes attached, inexplicably, to the paramesonephric duct at the uterotubal junction. Formation of the uterovaginal primordium by caudal fusion of the paramesonephric ducts apparently carries the attached gubernaculum medially within the cover of the encompassing mesentery of the structures (ie, the parts of the developing broad ligament). This fibrous band of connective tissue eventually becomes 2 ligaments.
Cranially, the band is the proper ligament of the ovary, extending between the inferior pole of the ovary and the lateral wall of the uterus just inferior to the oviduct. Caudally, it continues as the uterine round ligament from a point just inferior to the proper ovarian ligament and extending through the inguinal canal to the labium majus.

D. ANOMALIES OF THE UTERINE TUBES (OVIDUCTS, FALLOPIAN TUBES)

The uterine tubes are derivatives of the cranial segments of the paramesonephric (müllerian) ducts, which differentiate in the urogenital ridge between the sixth and ninth weeks (Fig 4–7 and Fig 4–14). Ductal formation begins with invagination of the coelomic epithelium in the lateral coelomic bay (Fig 4–5). The initial depression remains open to proliferate and differentiate into the ostium (Fig 4–14). Variable degrees of duplication of the ostium sometimes occur; in such cases, the leading edges of the initial ductal groove presumably did not fuse completely or anomalous proliferation of epithelium around the opening occurred.
Absence of a uterine tube is very rare when otherwise normal ductal and genital derivatives are present. This anomaly has been associated with (1) ipsilateral absence of an ovary and (2) ipsilateral unicornuate uterus (and probable anomalous broad ligament). Bilateral absence of the uterine tubes is most frequently associated with lack of formation of the uterus and anomalies of the external genitalia. Interestingly, absence of the derivatives of the lower part of the müllerian ducts with persistence of the uterine tubes occurs more frequently than the reverse condition. This might be expected, as the müllerian ducts form in a craniocaudal direction.
Partial absence of a uterine tube (middle or caudal segment) also has been reported. The cause of partial absence is unknown, although several theories have been advanced. One theory holds that when the unilateral anomaly coincides with ipsilateral ovarian absence, a “vascular accident” might occur following differentiation of the ducts and ovaries. Obviously, various factors resulting in somewhat localized atresia could be proposed. From a different perspective, bilateral absence of the uterine tubes as an associated disorder in a female external phenotype is characteristic of testicular feminization syndrome (nonpersistence of the rest of the paramesonephric ducts, anomalous external genitalia, hypoplastic male genital ducts, and testicular differentiation with usual ectopic location).

E. ANOMALIES OF THE UTERUS

The epithelium of the uterus and cervix and the fibromuscular wall of the vagina are derived from the paramesonephric (müllerian) ducts, the caudal ends of which fuse medially to form the uterovaginal primordium. Most of the primordium gives rise to the uterus (Fig 4–18). Subsequently, the caudal tip of the primordium contacts the pelvic part of the urogenital sinus, and the interaction of the sinus (sinovaginal bulbs) and primordium leads to differentiation of the vagina. Various steps in this sequential process can go awry, such as (1) complete or partial failure of one or both ducts to form (agenesis), (2) lack of or incomplete fusion of the caudal segments of the paired ducts (abnormal uterovaginal primordium), or (3) failure of development after successful formation (aplasia or hypoplasia). Many types of anomalies may occur because of the number of sites for potential error, the complex interactions necessary for the development of the müllerian derivatives, and the duration of the complete process.
Complete agenesis of the uterus is very rare, and associated vaginal anomalies are usually expected. Also, a high incidence of associated structural or positional abnormalities of the kidney has been reported; there has been speculation that the initial error in severe cases may be in the development of the urinary system and then in the formation of the paramesonephric ducts.
Aplasia of the paramesonephric ducts (müllerian aplasia) is more common than agenesis and could occur after formation and interaction of the primordium with the urogenital sinus. A rudimentary uterus or a vestigial uterus (ie, varying degrees of fibromuscular tissue present) is most frequently accompanied by partial or complete absence of the vagina (see text that follows). As in uterine agenesis, ectopic kidney or absence of a kidney is frequently associated with uterine aplasia (in about 40% of cases). Uterine hypoplasia variably yields a rudimentary or infantile uterus and is associated with normal or abnormal uterine tubes and ovaries. Unilateral agenesis or aplasia of the ducts gives rise to uterus unicornis, whereas unilateral hypoplasia may result in a rudimentary horn that may or may not be contiguous with the lumen of the “normal” horn (uterus bicornis unicollis with one unconnected rudimentary horn; Fig 4–16). The status of the rudimentary horn must be considered for potential hematometra at puberty.
Anomalous unification caudally of the paramesonephric ducts results in many uterine malformations (Fig 4–16). The incidence of defective fusion is estimated to be 0.1–3% of females. Furthermore, faulty unification of the ducts has been cited as the primary error responsible for most anomalies of the female genital tract. Partial or complete retention of the apposed walls of the paired ducts can produce slight (uterus subseptus unicollis) to complete (uterus bicornis septus) septal defects in the uterus. Complete failure of unification of the paramesonephric ducts can result in a double uterus (uterus didelphys) with either a single or double vagina.

F. ANOMALIES OF THE CERVIX
Because the cervix forms as an integral part of the uterus, cervical anomalies are often the same as uterine anomalies. Thus, absence or hypoplasia of the cervix is rarely found with a normal uterovaginal tract. The cervix appears as a fibrous juncture between the uterine corpus and the vagina.

Embryology of the Urogenital System & Congenital Anomalies of the Female Genital Tract

2008-08-16T06:30:00.000-07:00

The adult genital and urinary systems are distinct both in function and in anatomy, with the exception of the male urethra. During development, however, these 2 systems are closely associated. Primordial elements in the urinary system participate in the formation of genital structures; this requisite initial developmental overlap of the 2 systems occurs during the 4–12 weeks after fertilization. The complexity of developmental events in these systems is evident by the incomplete separation of the 2 systems found in some congenital anomalies (eg, female pseudohermaphroditism with persistent urogenital sinus). For the sake of clarity, this chapter describes the embryology of each system separately, rather than following a strict developmental chronology.
This chapter also presents descriptive overviews of some congenital malformations of the female genital tract and, when possible, an explanation of their embryonic origins. In view of the complexity and duration of differentiation and development of the genital and urinary systems, it is not surprising that the incidence of malformations involving these systems is one of the highest (10%) of all body systems. Etiologies of congenital malformations are sometimes categorized on the basis of genetic, environmental, or genetic-plus-environmental (so-called polyfactorial inheritance) factors. Known genetic and inheritance factors reputedly account for about 20% of anomalies detected at birth, aberration of chromosomes for nearly 5%, and environmental factors for nearly 10%. The significance of these statistics must be viewed against reports that (1) an estimated one-third to one-half of human zygotes are lost during the first week of gestation and (2) the cause of possibly 70% of human anomalies is unknown. Even so, congenital malformations remain a matter of concern because they are detected in nearly 6% of infants, and 20% of perinatal deaths are purportedly due to congenital anomalies.
The inherent pattern of normal development of the genital system can be viewed as one directed toward somatic “femaleness,” unless development is directed by factors for “maleness.” The presence and expression of a Y chromosome (and its testis-determining genes) in a normal 46, XY karyotype of somatic cells directs differentiation toward a testis, and normal development of the testis makes available its steroidal and proteinaceous hormones for the selection and differentiation of the genital ducts. In the normal absence of these testicular products, the “female” paramesonephric (müllerian) ducts persist. Normal feminization or masculinization of the external genitalia is also a result of the respective timely absence or presence of androgen.
An infant usually is reared as female or male according to the appearance of the external genitalia. However, genital sex is not always immediately discernible, and the choice of sex of rearing can be an anxiety-provoking consideration. Unfortunately, even when genital sex is apparent, later clinical presentation may unmask disorders of sexual differentiation that can lead to problems in psychological adjustment. Whether a somatic disorder is detected at birth or later, investigative backtracking through the developmental process is necessary for proper diagnosis and treatment.
OVERVIEW OF THE FIRST FOUR WEEKS OF DEVELOPMENT*
The transformation of the bilaminar embryonic disk into a trilaminar disk composed of ectoderm, mesoderm, and endoderm (the 3 embryonic germ layers) occurs during the third week by a process called gastrulation (Fig 4–1). All 3 layers are derived from epiblast. During this process, a specialized longitudinal thickening of epiblast, the primitive streak, forms near the margin (future caudal region) of the bilaminar disk and eventually elongates cephalad through the midline of the disk and extends to the central region. Some epiblastic cells migrate medially through a midline depression of the streak, to the ventral aspect of the streak, after which they become mesoblastic cells. The mesoblastic cells migrate peripherally between most of the epiblast and the hypoblast, forming the middle layer (embryonic mesoderm) of the now trilaminar disk. Other mesoblastic cells migrate into the hypoblastic layer, causing lateral displacement of most, if not all, of the hypoblastic cells. This new ventral layer of the disk becomes the embryonic endoderm. With formation of the new mesodermal layer, the overlying epiblast becomes the embryonic ectoderm, of which the medial part gives rise to neuroectoderm, the forerunner of the neural tube and neural crest (ie, the nervous system). By the end of the third week, 3 clusters of embryonic mesoderm are organized on both sides of the midline-developing notochord and neural tube.
The medial cluster is a thickened longitudinal column of mesoderm called paraxial mesoderm, from which somites, and in turn much of the axial skeleton, will form. The lateralmost cluster is called lateral plate mesoderm, in which a space (or coelom) develops, creating dorsal and ventral mesodermal layers (Fig 4–2). The intermediate mesoderm is located between the paraxial and lateral plate mesoderm and is the origin of the urogenital ridge and, hence, much of the reproductive and excretory systems (Fig 4–3). The primitive streak regresses after the fourth week. Rarely, degeneration of the streak is incomplete and presumptive remnants form a teratoma in the sacrococcygeal region of the fetus (more common in females than in males).
Weeks 4 through 8 of development are called the embryonic period (the fetal period is from week 9 to term) because formation of all major internal and external structures, including the 2 primary forerunners of the urogenital system (urogenital ridge and urogenital sinus), begins during this time. During this period the embryo is most likely to develop major congenital or acquired morphologic anomalies in response to the effects of various agents. During the fourth week, the shape of the embryo changes from that of a trilaminar disk to that of a crescentic cylinder. The change results from “folding,” or flexion, of the embryonic disk in a ventral direction through both its transverse and longitudinal planes. Flexion occurs as midline structures (neural tube and somites) develop and grow at a faster pace than more lateral tissues (ectoderm, 2 layers of lateral plate mesoderm enclosing the coelom between them, and endoderm). Thus, during transverse folding, the lateral tissues on each side of the embryo curl ventromedially and join the respective tissues from the other side, creating a midline ventral tube (the endoderm-lined primitive gut), a mesoderm-lined coelomic cavity (the primitive abdominopelvic cavity), and the incomplete ventral and lateral body wall. Concurrent longitudinal flexion ventrally of the caudal region of the disk establishes the pouch-like distal end, or cloaca, of the primitive gut as well as the distal attachment of the cloaca to the yolk sac through the allantois of the sac (Fig 4–4).
A noteworthy point (see The Gonads, in text that follows) is that the primordial germ cells of the later-developing gonad initially are found close to the allantois and later migrate to the gonadal primordia. Subsequent partitioning of the cloaca during the sixth week results in formation of the anorectal canal and the urogenital sinus, the progenitor of the urinary bladder, urethra, vagina, and other genital structures (Fig 4–1 and Table 4–1; see Subdivision of the Cloaca & Formation of the Urogenital Sinus in following text).
Another consequence of the folding process is the repositioning of the intermediate mesoderm, the forerunner of the urogenital ridge. Laterally adjacent to developing somites (from paraxial mesoderm) before flexion, the intermediate mesoderm is located after flexion just lateral to the dorsal mesentery of the gut and in the dorsal wall of the new body cavity. Thickening of this intermediate mesoderm with subsequent bulging into the cavity will form the longitudinal urogenital ridge (Fig 4–1 and Fig 4–4). Thus, by the end of the fourth week of development, the principal structures (urogenital ridge and cloaca) and tissues that give rise to the urogenital system are present.

THE URINARY SYSTEM
Three excretory “systems” form successively, with temporal overlap, during the embryonic period. Each system has a different excretory “organ,” but the 3 systems share anatomic continuity through development of their excretory ducts. The 3 systems are mesodermal derivatives of the urogenital ridge (Fig 4–3 and Fig 4–4), part of which becomes a longitudinal mass, the nephrogenic cord. The pronephros, or organ of the first system, exists rudimentarily, is nonfunctional, and regresses during the fourth week. However, the developing pronephric ducts continue to grow and become the mesonephric ducts of the subsequent kidney, the mesonephros. The paired mesonephroi exist during 4–8 weeks as simplified morphologic versions of the third, or permanent, set of kidneys, and they may have transient excretory function. The permanent kidney, the metanephros, begins to form in response to an inductive influence of a diverticulum of the mesonephric ducts during the fifth week and becomes functional at 10–13 weeks. During nephric differentiation, the urogenital mass becomes suspended from the dorsal wall by a double-layered urogenital mesentery.

Pronephros
Segmented clusters of cells form in each urogenital ridge opposite the cervical somitic region and give rise to pronephric tubules. The lateral end of a tubule in one segment of the ridge grows caudally to fuse with the end of the pronephric tubule in the next segment, thus initiating the cephalic portion of each of the bilateral pronephric ducts (Fig 4–3). The pronephroi degenerate by the end of the fourth week, but, by initiating formation of pronephric ducts, they set in motion the developmental sequence for the formation of the permanent excretory ducts and kidneys. The pronephric ducts continue to grow caudally until week 5, when they contact and open into the lateral posterior wall of the cloaca.

Mesonephros
Development of the mesonephric glomerulotubular units begins while the pronephric tubules are regressing. Cells in each nephrogenic cord condense to form cell clusters just caudal to the pronephros and adjacent to the caudally growing pronephric duct (now called the mesonephric duct). Each cluster differentiates into a hollow mesonephric vesicle and then a mesonephric tubule. Subsequently, the lateral end of a tubule joins the mesonephric duct (Fig 4–4 and Fig 4–5), while the medial end of the tubule expands into a double-layered, cup-shaped primitive glomerular capsule (Bowman's capsule; Fig 4–6). The capsule is vascularized by a capillary tuft, the glomerulus, derived from the aorta. Proliferation of the tubule's midportion produces a primitive version of a convoluted tubule.
While differentiation of the mesonephros is taking place in the caudal region, regression of mature tubules in the cranial region is also occurring (Fig 4–7). This craniocaudal gradient of differentiation followed by regression can give the impression that the relatively large, ovoid mesonephric kidney “descends” along the posterior wall of the body cavity during the embryonic period. By the end of this period, most remaining mesonephric tubules and glomeruli have begun to degenerate. Some of these tubules (descriptively called epigenital mesonephric tubules) persist in the mesonephric region laterally adjacent to the developing gonad and will participate in formation of the gonad and the male ductuli efferentes (Fig 4–8). A few tubules at other levels may persist as vestigial remnants near the gonad and sometimes become cystic (see Fig 4–14 and Fig 4–15).
Differentiation of the caudal segment of the mesonephric ducts results in (1) incorporation of part of the ducts into the wall of the urogenital sinus (early vesicular trigone, see following text), and (2) formation of a ductal diverticulum, which plays an essential role in formation of the definitive kidney. If male sex differentiation occurs, the major portion of each duct becomes the epididymis, ductus deferens, and ejaculatory duct. Only small vestigial remnants of the duct sometimes persist in the female (Gartner's duct; duct of the epoophoron).

Metanephros (Definitive Kidney)
A. COLLECTING DUCTS

By the end of the fifth week, a ureteric bud, or metanephric diverticulum, forms on the caudal part of the mesonephric duct close to the cloaca (Fig 4–7). The bud gives rise to the collecting tubules, calices, renal pelvis, and ureter (Fig 4–3). The stalk of the elongating bud will become the ureter when the ductal segment between the stalk and the cloaca becomes incorporated into the wall of the urinary bladder (which is a derivative of the partitioned cloaca, see text that follows; Fig 4–9, Fig 4–10, Fig 4–11 and Fig 4–12). The expanded tip, or ampulla, of the bud grows into the adjacent metanephric mesoderm (blastema), and continued growth of the bud eventually relocates the ampulla and associated blastema dorsal to the mesonephros (ie, “retroperitoneal”).
Between week 6 and weeks 20–24, the ampulla subdivides, and successive divisions yield approximately 12–15 generations of buds, or eventual collecting tubules. From weeks 10–14, dilatation of the early generations of tubular branches successively produces the renal pelvis, the major calices, and the minor calices, while the middle generations form the medullary collecting tubules. The last several generations of collecting tubules grow centrifugally into the cortical region of the kidney between weeks 24 and 36.

B. NEPHRONS
Dorsocranial growth of the ureteric bud into the caudal end of the nephrogenic cord brings the bud into contact with the metanephric mesoderm, or metanephric blastema (Fig 4–7). The blastema becomes a caplike structure over the ampullated end of the bud, and continued maintenance of this intimate relationship is necessary for normal metanephric organogenesis. Formation of the definitive excretory units starts at about the eighth week. Blastemic cells are influenced by the ampulla to form clusters. Subsequent early stages of differentiation of the blastema are similar to those in the development of the mesonephric tubule.
The cell clusters form metanephric vesicles, which elongate and differentiate into metanephric tubules. Differential proliferation of segments of the midportion of the tubule produces the proximal and distal convoluted tubules, whereas the central midportion forms the loop of Henle (Fig 4–3). The loops eventually grow centripetally toward the developing medullary zone. The end of the nephric tubule nearest the ampulla of the subdividing bud joins the newly formed collecting duct of that bud. The other end of the metanephric tubule expands, infolds somewhat, and becomes the cup-shaped Bowman's capsule. The capsule is invaginated by a tuft of capillaries, the glomerulus. Formation of urine purportedly begins at about weeks 10–13, when an estimated 20% of the nephrons are morphologically mature.
The last month of gestation is marked by interstitial growth, hypertrophy of existing components of uriniferous tubules, and the disappearance of bud primordia for collecting tubules. Opinions differ about whether formation of nephrons ceases prenatally at about 28 or 32 weeks or, postnatally, during the first several months. If the ureteric bud fails to form, undergoes early degeneration, or fails to grow into the nephrogenic mesoderm, aberrations of nephrogenesis result. These may be nonthreatening (unilateral renal agenesis), severe, or even fatal (bilateral renal agenesis, polycystic kidney).

C. POSITIONAL CHANGES

Figure 4–13 illustrates relocation of the kidney to a deeper position within the posterior body wall, as well as the approximately 90-degree medial rotation of the organ on its longitudinal axis. Rotation and lateral positioning are probably facilitated by the growth of midline structures (axial skeleton and muscles). The “ascent” of the kidney between weeks 5 and 8 can be attributed largely to differential longitudinal growth of the rest of the lumbosacral area and to the reduction of the rather sharp curvature of the caudal region of the embryo. Some migration of the kidney may also occur. Straightening of the curvature may be attributable also to relative changes in growth, especially the development of the infraumbilical abdominal wall. As the kidney moves into its final position (lumbar 1–3 by the 12th week), its arterial supply shifts to successively higher aortic levels. Ectopic kidneys can result from abnormal “ascent.” During the seventh week, the “ascending” metanephroi closely approach each other near the aortic bifurcation. The close approximation of the 2 developing kidneys can lead to fusion of the lower poles of the kidneys, resulting in formation of a single horseshoe kidney, the ascent of which would be arrested by the stem of the interior mesenteric artery. Infrequently, a pelvic kidney results from trapping of the organ beneath the umbilical artery, which restricts passage out of the pelvis.

THE GENITAL SYSTEM
Sexual differentiation of the genital system occurs in a basically sequential order: genetic, gonadal, ductal, and genital. Genetic sex is determined at fertilization by the complement of sex chromosomes (ie, XY specifies a genotypic male and XX a female). However, early morphologic indications of the sex of the developing embryo do not appear until about the eighth or ninth week after conception. Thus, there is a so-called indifferent stage, when morphologic identity of sex is not clear or when preferential differentiation for one sex has not been imposed on the sexless primordia. This is characteristic of early developmental stages for the gonads, genital ducts, and external genitalia. When the influence of genetic sex has been expressed on the indifferent gonad, gonadal sex is established. The SRY (sex-determining region of the Y chromosome) gene in the short arm of the Y chromosome of normal genetic males is considered the best candidate for the gene encoding for the testis-determining factor (TDF). TDF initiates a chain of events that results in differentiation of the gonad into a testis with its subsequent production of anti-müllerian hormone and testosterone, which influences development of somatic “maleness” (see Testis, in following text). Normal genetic females do not have the SRY gene, and the early undifferentiated medullary region of their presumptive gonad does not produce the TDF (see Ovary).
The testis and ovary are derived from the same primordial tissue, but histologically visible differentiation toward a testis occurs sooner than that toward an ovary. An “ovary” is first recognized by the absence of testicular histogenesis (eg, thick tunica albuginea) or by the presence of germ cells entering meiotic prophase between the eighth and about the 11th week. The different primordia for male and female genital ducts exist in each embryo during overlapping periods, but establishment of male or female ductal sex depends on the presence or absence, respectively, of testicular products and the sensitivity of tissues to these products. The 2 primary testicular products are androgenic steroids (testosterone and nonsteroidal anti-müllerian hormone (see Testis). Stimulation by testosterone influences the persistence and differentiation of the “male” mesonephric ducts (wolffian ducts), whereas anti-müllerian hormone influences regression of the “female” paramesonephric ducts (müllerian ducts). Absence of these hormones in a nonaberrant condition specifies persistence of müllerian ducts and regression of wolffian ducts, ie, initiation of development of the uterus and uterine tubes. Genital sex (external genitalia) subsequently develops according to the absence or presence of androgen. Thus, the inherent pattern of differentiation of the genital system can be viewed as one directed toward somatic “femaleness” unless the system is dominated by certain factors for “maleness” (eg, gene expression of the Y chromosome, androgenic steroids, and anti-müllerian hormone).

THE GONADS

Indifferent (Sexless) Stage
Gonadogenesis temporally overlaps metanephrogenesis and interacts with tissues of the mesonephric system. Formation of the gonad is summarized schematically in Fig 4–8.
About the fifth week, the midportion of each urogenital ridge ventromedially adjacent to the mesonephros thickens as cellular condensation forms the gonadal ridge (Fig 4–6). For the next 2 weeks, this ridge is an undifferentiated cell mass, lacking either testicular or ovarian morphology. As shown in Fig 4–8, the cell mass consists of (1) primordial germ cells, which translocate into the ridge, and a mixture of somatic cells derived by (2) proliferation of the coelomic epithelial cells, (3) condensation of the underlying mesenchyme of part of the urogenital ridge, and (4) in-growth of mesonephric-derived cells. The epithelial cells are not confined to the coelomic surface because the basal lamina of the coelomic epithelium is discontinuous in the area of the gonadal ridge.
The mesonephric-derived cells enter the basal aspect of the undifferentiated gonad, and some of these cells move peripherally, while some epithelial cells penetrate the mesenchyme and move centrally. During the indifferent stage, the germ cells and different somatic cells “intermingle” in the compact mass of the primordium. Later differentiation of the gonadal primordium results from interaction of the germ cells and the 3 types of somatic cells listed above. The end of the gonadal indifferent stage in the male is near the middle of the seventh week, when a basal lamina delineates the coelomic epithelium and the developing tunica albuginea separates the coelomic epithelium from the developing testicular cords. The indifferent stage in the female ends around the ninth week, when the first oogonia enter meiotic prophase.
Primordial germ cells, presumptive progenitors of the gametes, become evident in the late third to early fourth week in the dorsocaudal wall of the yolk sac and the mesenchyme around the allantois. The allantois is a caudal diverticulum of the yolk sac that extends distally into the primitive umbilical stalk and, after embryonic flexion, is adjacent proximally to the cloacal hindgut. The primordial germ cells are translocated from the allantoic region (about the middle of the fourth week) to the urogenital ridge (between the middle of the fifth week and late in the sixth week). The mechanism of translocation is uncertain (perhaps partially by ameboid movement and also passively owing to positional change of tissues). It is not known whether primordial germ cells must be present in the gonadal ridge for full differentiation of the gonad to occur. The initial stages of somatic development appear to occur independently of the germ cells. Later endocrine activity in the testis, but not in the ovary, is known to occur in the absence of germ cells. The germ cells appear to have some influence on gonadal differentiation at certain stages of development.

Testis
During early differentiation of the testis, there are condensations of germ cells and somatic cells (see previous text), which have been described as platelike groups, or sheets. These groups are at first distributed throughout the gonad and then become more organized as primitive testicular cords. The cords begin to form centrally and are somewhat arranged perpendicular to the long axis of the gonad. In response to testis-determining factor (TDF), these cords will differentiate into Sertoli cells (see following text). The first characteristic feature of male gonadal sex differentiation is evident around week 8, when the tunica albuginea begins to form in the mesenchymal tissue underlying the coelomic epithelium. Eventually, this thickened layer of tissue causes the developing testicular cords to be separated from the surface epithelium and placed deeper in the central region of the gonad. The surface epithelium re-forms a basal lamina and later thins to a mesothelial covering of the gonad. The testicular cords coil peripherally and thicken as their cellular organization becomes more distinct. A basal lamina eventually develops in the testicular cords, although it is not known if the somatic cells, germ cells, or both are primary contributors to the lamina.
Throughout gonadal differentiation, the developing testicular cords appear to maintain a close relationship to the basal area of the mesonephric-derived cell mass. An interconnected network of cords, rete cords, develops in this cell mass and gives rise to the rete testis. The rete testis joins centrally with neighboring epigenital mesonephric tubules, which become the efferent ductules linking the rete testis with the epididymis, a derivative of the mesonephric duct. With gradual enlargement of the testis and regression of the mesonephros, a cleft forms between the 2 organs, slowly creating the mesentery of the testis, the mesorchium. The differentiating testicular cords are made up of primordial germ cells (primitive spermatogonia) and somatic “supporting” cells (sustentacular cells, or Sertoli cells). Some precocious meiotic activity has been observed in the fetal testis. Meiosis in the germ cells usually does not begin until puberty; the cause of this delay is unknown. Besides serving as “supporting cells” for the primitive spermatogonia, Sertoli cells also produce a glycoprotein, anti-müllerian hormone (AMH; also called müllerian-inhibiting substance). Antimüllerian hormone causes regression of the paramesonephric (müllerian) ducts, apparently during a very discrete period of ductal sensitivity in male fetuses. At puberty, the seminiferous cords mature to become the seminiferous tubules, and the Sertoli cells and spermatogonia mature.
Shortly after the testicular cords form, the steroid-producing interstitial (Leydig) cells of the extracordal compartment of the testis differentiate from stromal mesenchymal cells, probably due to anti-müllerian hormone. Mesonephric-derived cells may also be a primordial source of Leydig cells. Steroidogenic activity of Leydig cells begins near the tenth week. High levels of testosterone are produced during the period of differentiation of external genitalia (weeks 11–12) and maintained through weeks 16–18. Steroid levels then rise or fall somewhat in accordance with changes in the concentration of Leydig cells. Both the number of cells and the levels of testosterone decrease around the fifth month.

Ovary
A. DEVELOPMENT

In the normal absence of the Y chromosome or the sex-determining region of the Y chromosome (SRY gene; see The Genital System, above), the somatic sex cords of the indifferent gonad do not produce testis-determining factor (TDF). In the absence of TDF, differentiation of the gonad into a testis and its subsequent production of anti-müllerian hormone and testosterone do not occur (see Testis, above). The indifferent gonad becomes an ovary. Complete ovarian differentiation seems to require 2 X chromosomes (XO females exhibit ovarian dysgenesis, in which ovaries have precociously degenerated germ cells and no follicles and are present as gonadal “streaks”). The first recognition of a developing ovary around weeks 9–10 is based on the temporal absence of testicular-associated features (most prominently, the tunica albuginea) and on the presence of early meiotic activity in the germ cells.
Early differentiation toward an ovary involves mesonephric-derived cells “invading” the basal region (adjacent to mesonephros) and central region of the gonad (central and basal regions represent the primitive “medullary” region of the gonad). At the same time, clusters of germ cells are displaced somewhat peripherally into the “cortical” region of the gonad. Some of the central mesonephric cells give rise to the rete system that subsequently forms a network of cords (intraovarian rete cords) extending to the primitive cortical area. As these cords extend peripherally between germ clusters, some epithelial cell proliferations extend centrally, and some mixing of these somatic cells apparently takes place around the germ cell clusters. These early cordlike structures are more irregularly distributed than early cords in the testis and not distinctly outlined. The cords open into clusters of germ cells, but all germ cells are not confined to cords. The first oogonia that begin meiosis are located in the innermost part of the cortex and are the first germ cells to contact the intraovarian rete cords.
Folliculogenesis begins in the innermost part of the cortex when the central somatic cells of the cord contact and surround the germ cells and an intact basal lamina is laid down. These somatic cells are morphologically similar to the mesonephric cells that form the intraovarian rete cords associated with the oocytes and apparently differentiate into the presumptive granulosa cells of the early follicle. Folliculogenesis continues peripherally. Between weeks 12 and 20 of gestation, proliferative activity causes the surface epithelium to become a thickened, irregular multilayer of cells, and in the absence of a basal lamina, the cells and apparent epithelial cell cords mix with underlying tissues. These latter cortical cords often retain a connection to and appear similar to the surface epithelium. The epithelial cells of these cords probably differentiate into granulosa cells and contribute to folliculogenesis, although this is after the process is well under way in the central region of the gonad. Follicles fail to form in the absence of oocytes or with precocious loss of germ cells, and oocytes not encompassed by follicular cells degenerate.
Stromal mesenchymal cells, connective tissue, somatic cells of cords not participating in folliculogenesis, and a vascular complex form the ovarian medulla in the late fetal ovary. Individual primordial follicles containing diplotene oocytes populate the inner and outer cortex of this ovary. The rete ovarii may persist, along with a few vestiges of mesonephric tubules, as the vestigial epoophoron near the adult ovary. Finally, similar to the testicular mesorchium, the mesovarium eventually forms as a gonadal mesentery between the ovary and old urogenital ridge. Postnatally, the epithelial surface of the ovary consists of a single layer of cells continuous with peritoneal mesothelium at the ovarian hilum. A thin, fibrous connective tissue, the tunica albuginea, forms beneath the surface epithelium and separates it from the cortical follicles.

B. ANOMALIES OF THE OVARIES

Anomalies of the ovaries encompass a broad range of developmental errors from complete absence of the ovaries to supernumerary ovaries. The many variations of gonadal disorders usually are subcategorized within classifications of disorders of sex determination. Unfortunately, there is little consensus for a major classification, although most include pathogenetic consideration. Extensive, excellent summaries of the different classifications are offered in the references to this chapter.
Congenital absence of the ovary (no gonadal remnants found) is very rare. Two types have been considered, agenesis and agonadism. By definition, agenesis implies that the primordial gonad did not form in the urogenital ridge, whereas agonadism indicates the absence of gonads that may have formed initially and subsequently degenerated. It can be difficult to distinguish one type from the other on a practical basis. For example, a patient with female genital ducts and external genitalia and a 46, XY karyotype could represent either gonadal agenesis or agonadism. In the latter condition, the gonad may form but undergo early degeneration and resorption before any virilizing expression is made. Whenever congenital absence of the ovaries is suspected, careful examination of the karyotype, the external genitalia, and the genital ducts must be performed.
Descriptions of agonadism have usually indicated that the external genitalia are abnormal (variable degree of fusion of labioscrotal swellings) and that either very rudimentary ductal derivatives are present or there are no genital ducts. The cause of agonadism is unknown, although several explanations have been suggested, such as (1) failure of the primordial gonad to form, along with abnormal formation of ductal anlagen, and (2) partial differentiation and then regression and absorption of testes (accounting for suppression of müllerian ducts but lack of stimulation of mesonephric, or wolffian, ducts). Explanations that include teratogenic effects or genetic defects are more likely candidates in view of the associated incidence of nonsexual somatic anomalies with the disorder. The streak gonad is a product of primordial gonadal formation and subsequent failure of differentiation, which can occur at various stages. The gonad usually appears as a fibrous-like cord of mixed elements (lacking germ cells) located parallel to a uterine tube. Streak gonads are characteristic of gonadal dysgenesis and a 45, XO karyotype (Turner's syndrome; distinctions are drawn between Turner's syndrome and Turner's stigmata when consideration is given to the various associated somatic anomalies of gonadal dysgenesis). However, streak gonads may be consequent to genetic mutation or hereditary disease other than the anomalous karyotype.
Ectopic ovarian tissue occasionally can be found as accessory ovarian tissue or as supernumerary ovaries. The former may be a product of disaggregation of the embryonic ovary, and the latter may arise from the urogenital ridge as independent primordia.

The Role of Imaging Techniques in Gynecology

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Case Report
C.O. is a 29-year-old white female, who presented with a history of infertility for several years, followed by a history of recurrent pregnancy losses.
Her past medical and surgical histories were negative. Gynecologically, she was remarkable in that she reported severe dysmenorrhea for the previous several years relieved by NSAIDs (nonsteroidal anti-inflammatory drugs). Her gynecologist found a low luteal phase progesterone and treated her with 50 mg of clomiphene citrate (CC) days 5–9 of the cycle.
She responded very well to the medication with a conception. The pregnancy resulted in a spontaneous abortion 5 weeks later. No D&C was required and she recovered well. She was still unable to conceive on her own and was again placed on CC. Again, she conceived and again had a spontaneous abortion—this time at 7 weeks' gestation. No D&C was performed.
The patient was then evaluated for recurrent pregnancy losses. Karyotype was normal for both partners. Hormonal evaluation was normal with the exception of a low mid-luteal phase progesterone. Immunologic and infectious screening also failed to reveal a cause for the recurrent losses. The hysterosalpingogram (HSG) demonstrated a midline filling defect similar to the one seen in Figure 3–1.

Figure 3–1. Müllerian anomaly as demonstrated by hysterosalpingogram. (Reproduced, with permission, from Doyle MB: Magnetic resonance imaging in müllerian fusion defects. J Reprod Med 1992;37:33.)

The patient was informed of the results and the potential for future miscarriages. The need for further evaluation and possible repair hysteroscopically or abdominally was carefully explained to the patient together with its risks and benefits. She elected to try CC one more time and hoped to avoid surgery.
At 8 weeks' gestation, vaginal ultrasonography revealed positive fetal cardiac activity in a CC-induced ovulation. While still on micronized progesterone, 100 mg 3 times daily, she was referred to her gynecologist for routine obstetric care.
At 12 weeks' gestation, the patient had an incomplete abortion that required a D&C. She recovered uneventfully and later returned to the office for further evaluation and treatment.
Several months were allowed to lapse before a hysteroscopy/laparoscopy revealed a broad-based intrauterine septum and stage I endometriosis. To evaluate the depth and width of the septum, a LaparoScan (EndoMedix, Irvine, CA) laparoscopic 7.5-Hz probe was used during the procedure. The septum was removed with a hysteroscopic resectoscope loop on a 40-watt setting. After the resection had been carried out, the ultrasonic probe was again used to measure the thickness of the myometrium and to verify the resection of the septum. A 30-mL 18F Foley catheter with the distal tip resected was placed in the fundus and inflated. The patient was discharged and placed on a broad-spectrum antibiotic and conjugated estrogen, 2.5 mg daily.

Discussion
As we entered the new millennium, a proliferation of imaging techniques used in medical practice occurred. Research into the development, refinement, and application of imaging in gynecology is very apparent in the literature.
The HSG has been considered the gold standard in the imaging of the uterine corpus for benign disorders (submucous myomas, submucous polyps, localization of tubal occlusion, and evaluation of müllerian fusion defects) and malignant disease (endometrial carcinoma).
In the case reported, the standard scout film was obtained and the cervix was prepared after the following were assured: the position of the uterus, absence of pelvic tenderness, and a negative pregnancy test. The water-soluble contrast medium was injected into the uterine cavity and oblique and anteroposterior films were obtained. These showed a midline uterine filling defect of the type usually seen with septate or bicornuate uteri.
Ultrasonography (US) performed on this patient during her pregnancies failed to show the filling defect. If suspected, the septum might have been encountered by more careful scanning. The scans of the last pregnancy revealed only an eccentrically placed pregnancy that might have been seen ultrasonographically even in normally structured uteri. Although not helpful at this point, ultrasonographic examination of the uterus between conceptions might have been helpful if used with a distending medium. This is especially useful in patients allergic to iodine contrast medium (Table 3–1). This technique of ultrasonic HSG is performed by occluding the cervix with a uterine injector and distending the uterus. This method can demonstrate the separate cavities as well as the possible difference between the septate and the bicornuate uterus while demonstrating tubal patency. The technique was adopted for this patient during her uterine septum resection to add ultrasonic contrast between the endometrial cavity and septum and the myometrium. Readers are referred to the many fine texts on diagnostic pelvic ultrasound for instruction and further discussion of these techniques. The development of “sonicated” contrast solutions may add greatly to the usefulness of US

Using 2 video cameras (one for the resectoscope and the other for the laparoscope and the LaparoScan laparoscopic ultrasound probe), all aspects of the surgery were evaluated. This setup allowed the operating surgeon adequate visualization of the uterine cavity during the resection and enabled other personnel in the operating room to follow the progress of the surgery. The laparoscopic video allowed the careful monitoring of the uterine surface and assured the surgeon that there would be less likelihood of a uterine perforation. This complication could have resulted in possible bowel injury.
The usefulness of the laparoscopic ultrasound probe with a picture within a picture was that it allowed the visualization of the 2 separate cavities and measurement of the length and width of the septum. It also enabled the operator to demonstrate the complete removal of the septum (Fig 3–2).

Figure 3–2. Uterine septum. A: Laparoscopic view shows a broad uterine fundus. B: Laparoscopic probe on the fundus of the uterus demonstrates the depth and width of the septum. C: Hysteroscopic view showing the resection of the uterine septum. D: Laparoscopic probe on the fundus of the uterus demonstrates the resected septum. (Note the echogenicity of the debris in the fundus.)

Imaging of the Uterus
Pelvic ultrasonography plays a significant role in the diagnosis of uterine leiomyomas (submucous, intramural, and subserosal) and polyps. The laparoscopic probe may be very useful in evaluating myomas during surgery for more accurate assessment of location and vascularity. The feasibility of continuing the procedure may also be assessed by this method intraoperatively.
Occasionally, the detection and localization of myomas, assessment of size, and their differential diagnosis are difficult. In these circumstances it is sometimes useful to perform magnetic resonance imaging (MRI) of the pelvis. MRI can accurately measure the volume of the myoma. This is an aid in determining whether medical management of myomas has resulted in shrinkage or if conservatively treated myomas are growing. Malignant degeneration of myomas visualized by MRI as described by some authors allows for early and appropriate intervention.
MRI also may be useful in the differential diagnosis of myomas and adenomyosis, benign and malignant ovarian pathology, pelvic kidney, and pelvic abscess.
One team of researchers described MRI of müllerian defects as an effective method of discerning between the septate and the bicornuate uterus, thus avoiding the more costly laparoscopy. In patients with very complicated müllerian fusion defects (didelphys with transverse vaginal septum or noncommunicating uterine segment), MRI may give a clear anatomic picture of the condition and allow for a properly planned surgical repair. If pelvic MRI had been performed on the patient in the case report that opens this chapter, it would probably have had the same appearance as the MRI in Figure 3–3. (Readers are referred to the review of MRI in müllerian fusion defects in Table 3–2.)

Imaging of the Endometrium
To obtain interobserver consistency in the evaluation of the endometrium, the following guidelines should be adhered to. Measurements are made in the midfundal region on the sagittal plane. Obtain the maximal double-thickness dimension, remembering to exclude the hypoechoic area between the myometrium and the endometrium and any fluid found between the anterior and posterior walls should be subtracted from the total measurement. The endometrium measures from 4–8 mm in thickness during the follicular phase. The uterine lining ranges from 7–14 mm during the luteal phase and has a uniform echogenic appearance.
Premenopausal women should be evaluated during the early follicular phase, immediately following the menses when the endometrium has a uniform linear appearance.
Menopausal women usually have an endometrial stripe of less than 4 mm. Menopausal women on hormone replacement therapy (HRT) may have endometrial thickness that exceeds 8 mm and a small amount of fluid (<> 4 mm.
In the future, three-dimensional ultrasound may be able to improve the diagnosis and staging of endometrial cancer.

Imaging of the Ovaries
About 12,000 women in the United States die annually as a result of ovarian cancer. Unfortunately, the ability of the pelvic examination to detect early ovarian malignancy is low. The same can be said of Ca-125 monoclonal marker for ovarian cancer, which has been found to be a poor predictor of early cases.
The flat plate of the abdomen may still be useful in the diagnosis of dermoid cysts of the ovary. However, cystic and solid structures of the ovary are now better evaluated by transabdominal ultrasonography (TAUS), transvaginal ultrasonography (TVUS), computed tomography (CT), and MRI.
Morphologic criteria have been assigned to increase suspicion concerning ultrasound findings when ovarian cancer is suspected. Cysts > 4 cm, solid and cystic components, septa, and papillary nodules have all been described.
TVUS combined with color flow and Doppler waveform was shown by Kurjak and colleagues to be sensitive and specific enough for application in an ovarian cancer screening program. Color flow allows the identification of vessels not previously identifiable with gray scale. With the use of the Doppler waveform, high- and low-resistance vessels in the ovaries can be distinguished. The resistance index (RI) is the systolic flow velocity peak minus the diastolic trough divided by the systolic peak. Using these techniques in 1000 women, these researchers were able to identify 83 women with the ultrasonographic signs or symptoms that led to surgery (Fig 3–4). Twenty-nine tumors were malignant, 4 from the asymptomatic group (Table 3–3). Color flow was not seen in only 2 of the malignant tumors. This demonstrates a sensitivity of 93% (Table 3–4). With a specificity of 65% for color flow alone, Doppler measurements are needed (Table 3–5). On the basis of distribution of RI values in benign and malignant tumors, a statistical cutoff value for the RI is 0.41 (Fig 3–5). The ability to identify malignant ovarian tumors with a combination of the above-mentioned techniques rather than the simpler laparoscopic approaches to benign adnexal disease may allow for more timely referral to gynecologic oncologists.

Not all studies are in agreement. A more recent evaluation of 47 patients with histologically proven ovarian cancer found that transvaginal color Doppler analysis of intratumoral blood flow didn't provide additional information concerning discriminatory characteristics when scanning individual tumors.
In an attempt to discriminate between malignant and benign adnexal masses in patients having color Doppler and serum Ca-125, one team of researchers developed a complementary multivariate logistic regression analysis. It was determined that the most useful variables among the 31 studied were the menopausal status, the serum Ca-125 level, the presence of one or more papillary growth (> 3 mm in length), and a color score indicative of tumor vascularity and blood flow. The model resulted in a sensitivity of 95.9% and a specificity of 87.1%. This team concluded that the use of a combination of diagnostic criteria and clinical information is more accurate than reliance solely on a single type of data.
CT may be useful for staging ovarian cancer preoperatively or for planning second-look procedures. In patients with benign-appearing adnexal masses (ovarian cysts or tubo-ovarian abscesses), CT may be very useful for biopsy and drainage. The contraindications to needle biopsy and drainage include lack of a safe unobstructed path for the needle, bleeding disorders, and lack of a motivated patient.

Imaging of the Fallopian Tubes
The best direct evaluation of the patency and architecture of the fallopian tubes is by means of endoscopic techniques. The best evaluation of tubal function indirectly is with HSG. This method allows demonstration of tubal patency and visualization of tubal rugations while avoiding the more costly laparoscopic surgery. Some disadvantages of HSG are pelvic infection, dye allergies, failure to detect adnexal adhesions, and false-positives for tubal occlusion. Hysterosalpingo-contrast sonography and MRI are also alternatives to laparoscopy, since women with normal findings probably have a normal pelvis.
The reader is referred to the sections on pelvic inflammatory disease and tubo-ovarian abscess elsewhere in this text for more on the radiographic diagnosis and management of these conditions.

Imaging in Ectopic Pregnancy
One team found that when human chorionic gonadotropin (hCG) levels reach 6500 mIU/mL, most normal intrauterine pregnancies can be detected as a gestational sac by TAUS. The value of adnexal sonography in the management of ectopic pregnancies was demonstrated by another set of researchers. They showed that if no gestational sac was seen on TAUS by 28 days and the hCG level was greater then 7500 mIU/mL, an ectopic gestation should be suspected. In a second related report, another team stated that the presence of fluid in the cul-de-sac and a noncystic adnexal mass had a predictive value of 94% in the diagnosis of ectopic pregnancy. However, the sonographic appearance of a pseudogestational sac should not be confused with the gestational sac. In the latter, a double-ring sign caused by the decidua parietalis is seen abutting the decidua capsularis.
TVUS, on the other hand, has the advantage of earlier and improved localization of the pregnancy with less pelvic discomfort since the bladder is not painfully distended. An hCG level of 1000 to 1500 mIU/mL (based on the International Reference Preparation) is the discriminatory zone in which an intrauterine pregnancy can be detected by TVUS. One must identify the double-ring sign of the intrauterine pregnancy and/or the yolk sac to ensure that the pregnancy is intrauterine. When an intrauterine pregnancy is not visualized on TVUS and the hCG level exceeds 1000–2000 mIU/mL, then suspicion for an ectopic pregnancy should be high. Also, multiple gestations may take several more days to be identified, and heterotopic pregnancies will be encountered more frequently in the patients using assisted reproductive techniques. The reader is referred to the section on ectopic pregnancy for a more complete discussion of this topic.
In a study of 71 patients with suspected ectopic pregnancies, one team failed to find an improvement in the diagnostic results when color Doppler imaging was used versus TVUS.
In the past decade, three-dimensional ultrasound has shown great promise in both obstetrics and gynecology. The technology is based on computer-generated three-dimensional images from a series of two-dimensional slices through the arc of tissue under the transducer. The resulting display shows longitudinal, transverse, and horizontal planes from which the 3-D image is calculated. This ever-improving technology is beginning to produce excellent imaging to detect uterine structural abnormalities. The precise size and location of polyps and myomas, as well as complete delineation of müllerian fusion defects have been reported. The 3-D measurements of ovarian pathology (with or without color Doppler) offers improved detection of early ovarian cancers with a greater degree of accuracy than the imaging techniques discussed here. Unfortunately, these techniques require a great deal of time and skill to produce these images, and they will require more refinement before they replace the widely used 2-D images.

Conclusion
The imaging techniques prevalent today have proven to be valuable tools in the diagnosis and early treatment of benign and malignant gynecologic disorders. To provide the patient with the highest level of medical care, the contemporary practicing gynecologist must constantly keep abreast of the new developments and applications of diagnostic imaging.
No matter what technology is used today and in the future, the goal will always be the same: to provide quick, low-risk, accurate diagnosis of gynecologic conditions, while keeping in mind the cost-effectiveness of the care delivered.

Approach to the Patient

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An effective relationship between health care provider and patient is based on the knowledge and skill that qualify the provider for effective communication between the individuals, and for the ethical standards that govern the conduct of the participants in the relationship.

THE KNOWLEDGE BASE
The health care of women encompasses all aspects of medical science and therapeutics. Physicians in the practice of obstetrics and gynecology are called upon as consultants, and in addition, they frequently act as primary care providers for their patients. Internists in general practice and family practitioners often find that a major component of their clinical activities involves the special needs of women. These special medical needs and concerns vary with the patient's reproductive status, her reproductive potential, and her desire to reproduce. Certainly the diagnostic possibilities and the choice of diagnostic or therapeutic intervention will be influenced by the possibility of, or desire for, pregnancy, or in some cases by the patient's hormonal profile. In addition, the gynecologic or obstetric assessment must include an evaluation of the patient's general health status and should be placed in the context of the psychologic, social, and emotional status of the patient.

History
To offer each woman optimal care, the information obtained at each visit should be as complete as possible. Whether the contact is a routine visit or is occasioned by a particular problem or complaint, the woman should be encouraged to view the visit as an opportunity to participate in improving her health. The clinical database should include general information about the patient and her goals in seeking care. The history of the present problem, past medical history, family history, medications used, allergies, and review of systems should be concise but thorough. Portions of the history provided by questionnaire or by other members of the health care team should be reviewed with the patient, in part to verify the information, but also to begin assessing the patient's personality and to determine her attitude toward the health care system. The menstrual history and developmental history may provide a background for presenting complaints in subsequent years. The menstrual history, sexual history, and obstetric history obviously assume central importance for the gynecologic or obstetric visit. In addition, the habit of systematically categorizing the nature of such complaints as pain, abnormal bleeding, or vaginal discharge will usually narrow the differential diagnoses. For example, the categorization of a complaint of pain should include its onset, duration, frequency, and associated behaviors, as well as a description of the nature or type of pain and its location. Such thoroughness will permit assessment of change as well as determination of the appropriate mode of investigation or therapy.
The initial contact with the patient, made while she is fully clothed and comfortable, may be useful in decreasing her anxiety about the physical examination; concerns about the examination may be elicited, and a history of previous unfortunate experiences may alert the examiner to the need for extra attention, time, and gentleness.

Physical Examination
The second component of the patient assessment, the physical examination, should also be directed toward evaluation of the total patient. The patient should again be encouraged to view the examination as a positive opportunity to gain information about her body, and she should be offered feedback regarding the general physical examination and any significant findings. The examination should always include a discussion of any concerns expressed by the patient. The breast examination provides a good opportunity to reinforce the practice of breast self-examination. The pelvic examination is usually an occasion of heightened anxiety for the patient, and every effort should be made to make the experience a positive one. The physician should give the patient as much control over the process as possible, by asking if she is ready, asking for feedback on whether the examination is painful, and seeking her cooperation in relaxation and muscle control. Information about each step of the examination can be provided so the patient is involved and appropriately aware of the value of each maneuver.
Inspection of the external genitalia is followed by the gentle insertion of an appropriately sized, warmed speculum to permit inspection of the vagina and the cervix. For patients with pain or increased anxiety, their cooperation must be continually reinforced by slow, gentle placement of the instrument, maintaining downward pressure against the relaxed perineal body and away from the urethral and anterior vaginal areas. Some women may wish to watch, by the use of a mirror, as the genitalia are inspected and may gain confidence from visualizing the cervix and vagina. The Papanicolaou (Pap) smear may be uncomfortable for some women, and they should be alerted when the test is being done. The bimanual examination should also be explained to the patient. When the uterus is anteflexed, the woman may want to appreciate the size and location of her uterus by feeling it with the guidance of the examiner. The rectovaginal and rectal examinations, if performed while the patient relaxes her anal sphincter, provide additional information and can be another source of reassurance for the normal patient or a means of diagnosis for the patient with disease. If an ultrasound is indicated as part of the gynecologic or obstetric examination, additional participation by the patient in the evaluation can be obtained by explanations of the visualized anatomy.

Implications of Technology
The scientific knowledge base for obstetric and gynecologic care has grown in parallel with general medical advances. In some cases this proliferation of information and technology has profoundly altered the relationship between health care providers and their patients. For example, the change from an intuitive management of labor and delivery to active monitoring and subsequent interpretation of data has provided a more rational basis for decision making. This change of management style has also created a potential for conflict or confusion in the relationship between patient and physician. In seeking to obtain additional information, the physician can be perceived to be intervening unnecessarily. More than ever before, issues of consumerism and participation in decision making require an understanding of the expectations of each individual woman. Whether a woman perceives herself as a “client” or as a “patient,” and the degree to which this perception coincides with the views of her physician, may alter her acceptance of recommendations for care. The fact that several options are available in the management of many obstetric or gynecologic situations may further complicate the relationship. However, this situation provides an opportunity to allow the patient to participate actively in choosing the best therapy for her particular circumstance.

COMMUNICATION
If the first foundation of a strong therapeutic relationship is knowledge, the second is communication. The ability to establish trust, to obtain and deliver complete and accurate information, and to ensure compliance with recommendations depends in large measure on the health care provider's communication skills. In some individuals these skills are innate, but for most the ability to become an effective communicator in a variety of settings requires an active process of learning and a willingness to be evaluated by peers. The information communicated in each encounter, whether by written material, in face-to-face discussion, or by telephone contact, extends beyond the factual content provided to include a demonstration of the provider's willingness to be available to answer questions and to encourage patient involvement in decision making.
One common barrier from the patient's perspective is that medical information is communicated via a foreign language to the layperson. This foreign language is often spoken in a hurried fashion and the listener is not given the opportunity to ask questions for clarification. The patient may also find it difficult to voice her concerns within the traditional doctor-patient relationship. She may be embarrassed to reveal intimate details of her personal life to a provider who does not take the time to show interest in her story. By not allowing the patient to express her fears, concerns, or questions, the provider can miss valuable clues to diagnosis and formulation of a treatment plan.
Solutions to these communication barriers can be found by educating patients and providers. The physician should provide a comfortable environment, encourage the patient to ask questions, listen carefully both to her story and the way she tells it, and explore with her the goals and expectations she has about the treatment. Videotaped interviews are a very effective means of educating providers about these skills. The patient should be asked to repeat instructions, and written material should be provided whenever possible. For her part the patient can be asked to take notes and keep a diary for review at subsequent visits.
Enhanced communication has been shown to dramatically increase compliance. A striking example of lack of compliance occurs with prescription of hormone replacement therapy (HRT). Overall compliance with HRT is approximately 30%. Patients either do not fill or renew their prescriptions because of fear of cancer or due to inadequate or inaccurate information regarding risks and side effects. Long-term continuance rates are highest among patients with the greatest understanding.
For the health care practitioner, the counterbalance of a litigious society that may hold the physician responsible for treatment outcome places a high premium on documentation and scientific justification for each intervention or nonintervention and can place the physician in an adversarial position with respect to the patient's desires. The obligation to inform the patient, to obtain surgical consent, or to advise about choices regarding pregnancy outcome, is becoming in some instances a matter of law rather than established medical practice. These legislative initiatives, while offensive to many, are signals that the public feels it requires protection from manipulation at the hands of those who have the power of knowledge and training not available to the layperson. Regardless of the validity of this perception, it can only be countered by efforts to establish and maintain the trust of each individual with whom the physician has a medical relationship. This trust is rooted in the physician's medical knowledge and is maintained by conscientious structured lifetime learning, the frank assessment and acknowledgment of areas of ignorance, and the willingness to discuss with the patient what is known and what is uncertain.

ETHICS
If the bricks of the foundation of the relationship between physician and patient are knowledge and communication, the mortar that forms the basis for trust is the integrity and ethical behavior of all participants in the relationship. Ethical dilemmas in obstetrics and gynecology are receiving increasing recognition, particularly as they deal with the provocative issues surrounding the beginnings of life, the nature of parenting, and the control of individual patients over their own destiny. Ethical dilemmas only arise when there are conflicting obligations, rights, or claims. Since the delivery of health care involves multiple participants, a consensus of values must often be sought when the patient is cared for by a team, even when significant pluralism of views might be represented. To minimize potential ethical conflicts, to anticipate potential areas of difficulty, and to achieve consistency in behavior, individuals may avail themselves of a number of resources for ethical decision making. In addition to the growing literature in the field, many hospitals and practice settings have formal consultation services for resolution of ethical dilemmas. Before seeking an external framework, however, the practitioner should be aware of his or her own values and understand the basis of these values. The values of the medical profession and of the institutions in which the physician practices, as formulated by codes and standards, but also as expressed indirectly through past actions, are usually then helpful in providing a decision-making framework. Finally, a familiarity with ethical theories may permit decision making that achieves an acceptable consensus in the face of conflicting values. Discussions based on consideration of the ethical principles of patient autonomy (respect for persons), beneficence (doing good), nonmaleficence (refraining from doing harm), and justice (consideration of resources and fairness of opportunity) will prevent capricious and arbitrary decisions.
The principle of autonomy, or respect for each individual person, may form the underlying basis for resolving many ethical questions and will determine appropriate attitudes toward confidentiality, privacy, right to information, and the ultimate primacy of the patient in making treatment decisions. Since caring for women necessarily involves information regarding sensitive and intimate relationships and activities, as well as access to a woman's thoughts, feelings, and emotions, full disclosure of such information by the patient places a burden of trust on the health care provider to protect the rights and privacy of each patient. The relationship established at an initial gynecologic visit between a young adolescent and the physician may potentially extend throughout her adult life and include such major life events as education about reproductive health, assistance in family planning and childbearing, and preservation of physical fitness and well-being through the postmenopausal years. To successfully establish such an enduring clinical relationship requires a sensitivity to the changing goals and needs of the individual patient. Offering care to some patients or providing some types of services may not be comfortable for all practitioners. For example, establishing a rapport with an adolescent seeking birth control or providing health care for a lesbian woman may require a nonjudgmental approach when one is interviewing the patient and a balanced consideration of lifestyle options. The recognition of these special needs has led to a compartmentalization of health care in some regions, so that specialty practices or clinics directed toward adolescent health care, family planning, fertility, oncology, and menopausal care are frequently available. These resources can best be utilized by referral, with guidance provided by a primary provider, so that appropriate use of such resources can be an integral part of the general health care of each woman.