Abstract
The forties are a time of irregular and sometimes heavy menstrual loss due to fluctuating levels of sex hormones. Some months are characterized by low estrogen secretion and anovulation and others by extremely high levels of estradiol (E2). In a 20-year-old woman, E2 usually peaks at 500–1000 pmol/L. In contrast, some perimenopausal women may have cycles where E2 levels peak at around 5000 pmol/L. These high levels of estrogen are often not followed by ovulation and so progesterone is either not secreted at all, or levels are too low to counter these high-estrogen months. As we will see shortly, many gynecologic pathologies are driven by these unbalanced sex hormone levels.
The forties are a time of irregular and sometimes heavy menstrual loss due to fluctuating levels of sex hormones. Some months are characterized by low estrogen secretion and anovulation and others by extremely high levels of estradiol (E2). In a 20-year-old woman, E2 usually peaks at 500–1000 pmol/L. In contrast, some perimenopausal women may have cycles where E2 levels peak at around 5000 pmol/L. These high levels of estrogen are often not followed by ovulation and so progesterone is either not secreted at all, or levels are too low to counter these high-estrogen months. As we will see shortly, many gynecologic pathologies are driven by these unbalanced sex hormone levels.
The perimenopause is also a time when gynecologic pathology is common. By age 40 years, around one in three women will have at least one fibroid; adenomyosis and endometriosis are also common. All three of these conditions are driven by sex hormones and are cured by menopause. Prior to the advent of the levonorgestrel-containing intrauterine system (LNG-IUS) and endoscopic surgery, as many as one in three women had an abdominal or vaginal hysterectomy for painful, heavy periods associated with fibroids, adenomyosis and/or endometriosis.
Abnormal uterine bleeding is very common at this stage of life. Apart from the conditions already mentioned, the endometrium is often the target of pathology as well. Polyps are common and can cause pain and bleeding. Potentially more sinister, endometrial hyperplasia can be a precursor to endometrial carcinoma. In contrast to younger women, where the vast majority of ovarian cysts are benign and transient, in this age group, persistent, premalignant cysts are common.
In this chapter, we will examine the pathophysiology of those gynecologic conditions that can cause significant distress for the woman who is approaching her menopause. First, the pathophysiology of these pathologies will be considered and then second, the various clinical presentations.
Pathology
Fibroids
Fibroids are benign fibromuscular tumours arising from the myometrium. Some are very slow growing, but occasionally they can grow rapidly. Malignant transformation into a sarcoma is possible but exceedingly rare (around 1/1000). The site of the fibroid is critically important. Those that are intramural or growing subserosally (under the uterine serosa) are less likely to result in menorrhagia than those inside the uterine cavity (intracavity) or under the endometrium (submucus).
Beneath the endometrium is a rich plexus of blood vessels. Thus, a fibroid that is growing towards the uterine cavity will ‘push’ these vessels ahead of it. Hysteroscopic examination of such a submucus fibroid typically shows large vessels coursing over the benign tumour. When these vessels bleed, haemorrhage can be quite vigorous. Submucus fibroids can become pedunculated over time and so crampy pain is common. Occasionally pain can be severe, especially if the uterus attempts to pass a pedunculated fibroid through the cervix.
Fibroids probably arise from a somatic myometrial stem cell. They usually have estrogen receptors (ERs) and progesterone receptors (PRs). After menopause, with the loss of sex steroid drive, fibroids typically shrink, although some will become calcified.
Adenomyosis
Adenomyosis is defined by the presence of endometrial tissue within the uterine wall. It is probably due to the basalis layer of the endometrium growing into the myometrium. It usually affects the posterior wall of the uterus more than the anterior. Typically, the uterus is diffusely enlarged, although it is possible for adenomyosis to resemble a fibroid, producing a localized tumour (Figure 16.1). Adenomyosis usually hyperexpresses ER. It is often associated with fibroids, polyps and endometrial hyperplasia [1].
Figure 16.1 An ultrasound scan of an ovarian endometrioma. Note the homogenous appearance of the ovarian mass.
Endometriosis
This is an estrogen-dependent inflammatory disease that affects around 10 per cent of reproductive-aged women. It is typified by the presence of endometrial-like tissue found outside the endometrial cavity, often associated with bleeding and inflammation (leading to scarring). The inflammation can irritate nerve fibres causing severe pain, as well as damaging adjacent structures such as the fallopian tubes (leading to blockage) or bowel (leading to pain and rectal bleeding). Infertility may result from the factors already mentioned or by adverse effects on uterine receptivity, sperm function or even the embryo itself. There may be a link with ovarian cancer.
Blood levels of CA-125 can be elevated in cases of endometriosis, but the only sure method of diagnosis is visual, usually by laparoscopy. The lesions are typically black or red but can be clear and are often seen on the pelvic peritoneum, especially the Pouch of Douglas, on the ovaries, bladder, bowel and uterine serosa. It can form (chocolate-) cysts within the ovary. There does appear to be a link between endometriosis and other autoimmune conditions [2].
The etiology of endometriosis still remains elusive. One theory speculates that endometrial cells implant on the peritoneum because of retrograde menstruation. Another theory suggests that the disease is the result of celomic metaplasia. It can be inherited in a polygenic way and it often runs in families. Endometriosis usually hyperexpresses ER; whereas PR is usually downregulated and within the lesions, aromatase is hyperexpressed also. Prostaglandins are produced in high amounts by the endometriotic tissue and so contribute to the pain and inflammation.
Simple Ovarian Cysts
These are benign tumours, greater than 4–5 cm in diameter with a simple thin capsule and no internal solid features. As in younger patients, if they are ovulation-type cysts, they typically resolve in a couple of months. Cystadenomas are increasingly common as women age and are seen in this age group. Most are of a serous or mucinous type. They do not resolve spontaneously, but rather increase in size over time and can become malignant.
Most serous tumours are predominantly cystic and less solid. Inside the cystic component are papillary structures and grossly, they can resemble ovarian cancer but without invasion or atypia. Microscopically, there are small uni- or multilocular cysts lined by a single layer of tall, columnar, ciliated cells resembling normal tubal epithelium, or cuboidal non-ciliated cells resembling ovarian surface epithelium. In a third of cases they are bilateral. Autoimplants may occur on the ovarian surface that appear identical to non-invasive desmoplastic (serous epithelium with or without Psammoma bodies within abundant fibrous or granulation-like tissue) changes that can occur outside the ovary (e.g. on the fallopian tube).
Mucinous cystadenomas can grow very large and mimic fibroids or even pregnancy from localized pressure in the pelvis or abdomen. The epithelium is usually tall and columnar with basal nuclei and abundant intracellular mucin. Stroma may be fibrous. Calcifications and microscopic cyst rupture may be present. Around 5 per cent are bilateral. If the tumour ruptures (spontaneously or at surgery), spill into the peritoneal cavity can result in pseudomyxoma peritonei (a gelatinous type of ascites).
Solid or Complex Ovarian Cysts
Solid or complex ovarian cysts are fluid-filled structures with a diameter greater than 4–5 cm which also contain some internal solid tissue (Figure 16.2). A corpus luteum can appear as a complex ovarian cyst but will resolve over time. The differential diagnosis of a growing complex cyst includes a dermoid (teratoma; containing skin, neuronal tissue, teeth, hair, etc.), ovarian cancer or an endometrioma (an ovarian cyst of endometriosis; a so-called chocolate cyst) [3].
Figure 16.2 A complex ovarian mass as seen on ultrasound. Fluid shows up as ‘black’ on ultrasound. This mass has both cystic and solid features.
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