Normal and Abnormal Uterine Bleeding
Diana Broomfield
Alicia Armstrong
David Carnovale
William J. Butler
DEFINITIONS
Amenorrhea—The absence of menstrual bleeding for more than 6 months.
Breakthrough bleeding—Intermenstrual bleeding that occurs despite the use of exogenous hormones.
Dysmenorrhea—Painful menstruation.
Interval bleeding—Bleeding between menstrual cycles.
Menorrhagia—Prolonged menstrual bleeding that is excessive in amount, duration, or both that occurs at regular intervals.
Metrorrhagia—Bleeding between periods.
Oligomenorrhea—Bleeding that occurs less frequently than every 35 days.
Polymenorrhea—Bleeding that occurs more often than every 21 days.
Postmenopausal bleeding—Uterine bleeding occurring more than 12 months after the last menstrual period of a menopausal woman.
PALM-COEIN—Polyp; adenomyosis; leiomyoma; malignancy and hyperplasia; coagulopathy; ovulatory dysfunction; endometrial; iatrogenic; and not yet classified. The term dysfunctional uterine bleeding (DUB) is discouraged since the implementation of this classification system.
INTRODUCTION
Abnormal uterine bleeding (AUB) is an extremely common gynecologic complaint. It is estimated that 30% of women experience menorrhagia annually. This debilitating condition is clinically important; Mahoney and colleagues report it is the indication for two thirds of hysterectomies and nearly 25% of gynecologic operations. Thus, the impact of this condition on the public health and health care costs is significant. Because medical therapies for AUB have significant failure rates or side effects, surgical treatment by hysterectomy remains a major therapeutic option for chronically symptomatic women. This chapter reviews normal menstruation, the pathophysiology underlying AUB, the evaluation of AUB, and current treatment modalities.
Reproductive capability in a young woman begins at the point of menarche, which is the beginning of cyclic uterine bleeding in the anatomically and physiologically normal female. Menarche marks the beginning of an important stage in a young woman’s physical reproductive maturation and development. Attitudes toward menstruation, what is considered “normal,” and the decision to seek medical evaluation are impacted by a variety of factors. In one cross-sectional US study of nearly 2,000 women, the authors concluded that Western cultures tend to “medicalize” menstruation, as evidenced by the media information that depicts menstruation as something that should be managed and remedied. This investigation also suggested that positive attitudes toward menstruation are
more prevalent among women with higher educational levels and higher incomes. Positive attitudes were more common among women who exercised frequently and older women who were approaching menopause. Race and ethnicity also played a role in attitudes toward menstruation with non-European Americans having a more positive attitude toward menstruation. Common wisdom would suggest, and studies support, the assumption that women who do not have an understanding of normal menstrual physiology are more likely to become alarmed about any disruption in what is perceived to be normal menstruation. As health care providers, it is our responsibility to educate our patients about what is normal and what symptoms would require medical evaluation. Current medical therapies are quite effective in the management of most of the disturbances of menstrual function that occur in the absence of infection, gestation, or uterine tumor. The success of these therapies depends on a complete understanding of normal menstrual physiology and of the effects of the various agents available for treatment. In addition, new surgical diagnostic and therapeutic technologies are becoming available to aid in the management of patients who fail to respond to conventional endocrine manipulation by medical therapies.
more prevalent among women with higher educational levels and higher incomes. Positive attitudes were more common among women who exercised frequently and older women who were approaching menopause. Race and ethnicity also played a role in attitudes toward menstruation with non-European Americans having a more positive attitude toward menstruation. Common wisdom would suggest, and studies support, the assumption that women who do not have an understanding of normal menstrual physiology are more likely to become alarmed about any disruption in what is perceived to be normal menstruation. As health care providers, it is our responsibility to educate our patients about what is normal and what symptoms would require medical evaluation. Current medical therapies are quite effective in the management of most of the disturbances of menstrual function that occur in the absence of infection, gestation, or uterine tumor. The success of these therapies depends on a complete understanding of normal menstrual physiology and of the effects of the various agents available for treatment. In addition, new surgical diagnostic and therapeutic technologies are becoming available to aid in the management of patients who fail to respond to conventional endocrine manipulation by medical therapies.
The normal interval between menstrual cycles is 21 to 35 days, and the normal duration is generally 5 days. Although heavy bleeding has been traditionally described as a blood loss exceeding 80 mL, a more practical approach is to rely upon the patient’s perception. The term menorrhagia has been used to define heavy bleeding, while metorrhagia is used to define bleeding between periods. Oligomenorrhea is used to describe bleeding that occurs less frequently than every 35 days, and polymenorrhea is used to define bleeding that occurs more often than every 21 days.
In 2011, in an effort to standardize the nomenclature used to describe uterine bleeding abnormalities, a new classification system was introduced by the International Federation of Gynecology and Obstetrics (FIGO). The classification system known by the acronym PALM-COEIN (polyp; adenomyosis; leiomyoma; malignancy and hyperplasia; coagulopathy; ovulatory dysfunction; endometrial; iatrogenic; and not yet classified) is also supported by the American Congress of Obstetricians and Gynecologists.
The PALM-COEIN system differs from the previously used nomenclature in that it categorizes uterine bleeding by etiology as well as bleeding pattern. Under the new classification system, terms such as menorrhagia would be replaced by heavy menstrual bleeding. The PALM-COEIN system also uses letter qualifiers to identify the etiology (Fig. 26.1). Prior to the implementation of the PALM-COEIN classification system, the term dysfunctional uterine bleeding (DUB) was often used interchangeably with AUB; DUB was used to indicate AUB for which there was no systemic or structural etiology. The use of the term DUB is not part of the PALM-COEIN system, and its use is discouraged by the FIGO Working Group in 2011.
 FIGURE 26.1 PALM-COEIN classification system. |
MENSTRUAL PHYSIOLOGY
Menstruation is the physiologic shedding of the endometrium associated with uterine bleeding that occurs at monthly intervals from menarche to menopause. In the years between these two physiologic landmarks, menstruation will occur 400 to 500 times in the average woman. According to the classical theory of the physiology of menstruation, it is the superficial functional layer of the endometrium that is shed during menstruation, and regeneration proceeds from the remaining intact basalis.
Recent work in humans has confirmed the presence of endometrial stem cells, which most likely are located in niches within the basalis layer. Additionally, it appears that these progenitor cells are hormonally independent. The proliferative potential of these cells is maintained in the noncycling state as demonstrated by their ability to regenerate endometrium in postmenopausal women given hormone replacement therapy.
The regenerating properties of the endometrium and its ability to support and nourish a fertilized ovum are an extremely complex system that appears to involve numerous endocrine, paracrine, and autocrine interactions. At the endometrial level, all three inhibin subunits are expressed in the human. It is believed that these dimeric glycoproteins may be involved in endometrial maturation, such as angiogenesis, decidualization, and tissue remodeling. Epidermal growth factors (EGFs) are extremely important in human embryogenesis, development, and proliferation differentiation. Human endometrial cells have been shown to express all four EGF receptors and two ligands amphiregulin and transforming growth factor alpha. Other substances with known angiogenic properties, such as leptin and erythropoietin, have also been shown to be expressed along with their receptors by human endometrium.
This process of monthly shedding and regeneration can occur as often as it does without producing permanent tissue damage possibly because most of the functional endometrium is conserved during menses and because the metamorphosis from proliferative to secretory endometria is controlled not only by processes of cell desquamation and reproliferation but also by dynamic and interactive processes of the endocrinologic and reproductive systems involving many organs. Any interruption of these normal but quite complex cyclic processes can lead to irregularities in endometrial breakdown and to AUB; the categorization of type of AUB is determined by the PALM-COEIN classification system (Fig. 26.1).
ENDOCRINOLOGY
The endometrium is an endocrine organ that responds to circulating blood levels of estrogen and progesterone. These two steroids alone are sufficient to induce growth and maturation of an endometrium that can support blastocyst implantation, as has been demonstrated by their sequential administration to patients with ovarian failure to prepare for the transfer of donated embryos. Estradiol (E2) production by the developing follicle stimulates metabolic activity in the endometrium. E2 has multiple effects that are mediated through binding to estrogen receptors. There are two estrogen receptors: alpha and beta. The estrogen receptors are members of a hormone receptor family that includes not only the other steroid receptors but
also receptors for vitamin D and thyroid hormone. All receptors in this family have three domains. The regulatory domain at the amino acid terminal binds regulatory protein factors. The hormone-binding domain on the carboxy terminal, with its contiguous hinge region, undergoes conformational changes when a steroid hormone binds to it, allowing DNA binding. The DNAbinding domain binds to the hormone-responsive elements in the target gene. The conformation of the DNA-binding domain consists of the highly conserved zinc finger structures that interact with complementary patterns in the DNA.
also receptors for vitamin D and thyroid hormone. All receptors in this family have three domains. The regulatory domain at the amino acid terminal binds regulatory protein factors. The hormone-binding domain on the carboxy terminal, with its contiguous hinge region, undergoes conformational changes when a steroid hormone binds to it, allowing DNA binding. The DNAbinding domain binds to the hormone-responsive elements in the target gene. The conformation of the DNA-binding domain consists of the highly conserved zinc finger structures that interact with complementary patterns in the DNA.
Steroid hormones have relatively low molecular weights and are rapidly transported into cells by passive diffusion. Binding of a steroid hormone to the intranuclear receptors transforms and activates the hormone receptor complex to allow DNA binding to specific hormone response elements and initiates subsequent transcription. Both estrogen and progesterone receptors bind to their response elements as dimers. After gene activation, the hormone receptor complex undergoes processing with dissociation and loss of activity.
Transcription of target genes with mRNA synthesis leads to translation with synthesis of proteins on ribosomes in the cytoplasm. The biologic effects of E2 are mediated through this protein synthesis.
Estrogen and Progesterone Receptor Induction
One important function of estrogen is the induction of synthesis of its own and other steroid hormone receptors, called replenishment. Estrogen receptors reach a maximum concentration in the middle-to-late proliferative phase of the menstrual cycle. Progesterone receptors are also induced, and their concentration peaks in the late proliferative phase. Progesterone then blocks the estrogen replenishment mechanism, possibly by accelerating receptor turnover and inhibiting E2-induced gene transcription. Enough progesterone receptors persist throughout the luteal phase, however, to maintain endometrial responsiveness and induction of deciduation.
Estrogen and Progesterone Target Genes
Target genes of the E2 receptor complex code for the synthesis of numerous proteins, including structural proteins, enzymes, and growth factors. The relative roles played by the alpha and beta estrogen receptors in the endometrium have yet to be completely elucidated. The net effect of estrogenic stimulation is to induce DNA synthesis and mitotic activity with proliferation of the endometrial glands and stroma. The results are cessation of menstrual flow and an increase in the thickness of the endometrium.
Progesterone also has multiple biologic effects mediated through its receptors. It actively inhibits synthesis of both its own receptors and estrogen receptors, although sufficient progesterone receptors remain throughout the luteal phase of the cycle to mediate maturation and secretory differentiation of the endometrium. The net effect is to antagonize estrogenic metabolic activity with suppression of DNA synthesis in endometrial cells, which results in dynamic inhibition of cell mitosis. Progesterone is also responsible for the active induction of synthesis of various cytoplasmic enzymes, the secretion of proteins such as prolactin-dependent and progesterone-dependent endometrial peptide from decidualized stromal cells, and the stabilization of lysosomes, all of which may play an important role in the onset of menstruation.
Histology and Physiology
The postmenstrual endometrium that remains after collapse and partial shedding during menstruation consists of a thin but stable layer of basalis cells and the dense irregular remnants of the stromal cell-derived stratum spongiosum. The glands are narrow and lined by low cuboidal epithelial cells with few mitoses. The glandular stromal cells are small and spindle shaped with little cytoplasm or mitotic activity. Protein synthesis and secretory activity are minimal. It is on this substrate of basal and stromal cells that estrogen induces a proliferative response.
Early Proliferative Phase
Mitotic activity results in growth and pseudostratification of the glandular epithelial cells. With development and elongation of the glands, the epithelial cells assume a more columnar shape, with secretory granules in the cytoplasm, and glycogen begins to collect in the basal vacuoles. Arteriolar vessels grow up into the endometrium as part of the general proliferative response. The stromal cells also proliferate and expand from a dense compact state to an expanded matrix by transient edema. The combined effects of proliferation and expansion cause the endometrium to grow in this phase to a thickness of 3 to 5 mm.
The increased mitotic activity that results in proliferation is mediated by way of estrogen induction of various peptide growth factors. Epidermal growth factors and insulinlike growth factor I (IGF-I) are two potent mitogens with synthesis that is stimulated by estrogen in endometrial epithelial and stromal cells. Endothelin-1 is a vasoactive peptide with mitogenic activity; its synthesis is induced by both estrogen and growth factors, and its metabolism is enhanced by progesterone. Endothelin-1 may play a role in proliferation and in menstruation. The various peptides that are secreted from stromal and epithelial cells to form the extracellular matrix of the endometrium can be either induced or suppressed by both estrogen and progesterone. Fibronectin, for example, is suppressed by progesterone, whereas several integrin subtypes are stimulated by progesterone. These peptides may have a functional role in proliferation, differentiation, and embryo implantation.
Angiogenesis both allows repair of the endometrium after menstruation and supports cellular proliferation for regrowth during the follicular phase. It is supported and promoted by multiple growth factors. An important role is played by vascular endothelial growth factor (VEGF). Torry and Torry found VEGF mRNA expression is induced by E2 and increases from the early proliferative phase through the secretory phase. Vascular endothelial growth factor is produced by the glandular epithelial cells, although some stromal expression is evident in the secretory phase. The increased expression throughout the cycle supports a possible role of VEGF in expansion and coiling of the spiral arterials. Kooy et al. detected changes in VEGF in women with AUB, supporting a possible role in the pathogenesis of menorrhagia.
E2 induces several enzymes (alkaline phosphatase, 5α-reductase, and possibly phospholipase A2). Phospholipase A2, which releases arachidonic acid from phospholipid esters, controls the rate-limiting step in prostaglandin synthesis. E2 also stimulates cyclooxygenase synthesis of prostaglandin F2α (PGF2α) and prostaglandin E2 (PGE2), both of which have a role in menstrual function. PGF2α has vasoconstrictive and muscle contraction effects. PGE2 is generally a vasodilator but can also cause contractions in uterine smooth muscle. Alterations in the relative levels of PGF2α and PGE2 are known to change menstrual bleeding patterns.
Late Proliferative Phase
Ovulation with corpus luteum formation and significant progesterone secretion leads to secretory transformation in the
late proliferative phase endometrium. Progesterone inhibits both estrogen and progesterone receptor synthesis and inhibits DNA synthesis and mitosis. This inhibition process is accompanied by the development of RNA-filled channels between the nucleoli and nuclear membranes that are responsible for the progesterone-induced active synthesis of cytoplasmic enzymes during the secretory phase of the cycle.
late proliferative phase endometrium. Progesterone inhibits both estrogen and progesterone receptor synthesis and inhibits DNA synthesis and mitosis. This inhibition process is accompanied by the development of RNA-filled channels between the nucleoli and nuclear membranes that are responsible for the progesterone-induced active synthesis of cytoplasmic enzymes during the secretory phase of the cycle.
The Secretory Phase
The cytoplasmic enzymes 17β- and 20α-hydroxysteroid dehydrogenase (HSD) are induced by progesterone and modulate steroid activity. The enzyme 17β-HSD catalyzes the conversion of E2 to the relatively weaker estrogen estrone, which, when sulfated by estrogen sulfotransferase, can no longer bind to estrogen receptors. The enzyme 20α-HSD alters progesterone receptor binding and activity. Cytoplasmic lytic enzymes such as acid phosphatase are also induced by progesterone but are kept inactive within Golgi-derived lysosomes, the membranes of which are stabilized by progesterone. Insulin-like growth factor II is synthesized locally by middle-to-late secretory phase endometrium and appears to be involved in the differentiation response of the endometrium to progesterone. Insulinlike growth factor-binding protein I also appears at this time and is regulated by the IGFs and by relaxin. Other autocrine or paracrine agents secreted locally by decidual cells are relaxin, progesterone-dependent endometrial peptide, and prolactin.
Progesterone has also been shown to induce the activity of metalloendopeptidase, which degrades the endothelin-1 peptide. Withdrawal of progesterone can lead to increased endothelin-1 activity with vasospasm and initiation of menstrual bleeding. Several investigators have described increased levels of protease inhibitors, such as α1-antitrypsin and antithrombin III, in secretory phase uterine fluid, which may also be involved in the mechanism of menstrual bleeding.
The Luteal Phase
Morphologically, secretory transformation of the endometrium results in coiling of the spiral arterioles and endometrial glands. The endometrium reaches its maximum thickness of 5 to 6 mm and maintains this thickness throughout the luteal phase. The subnuclear intracytoplasmic glycogen vacuoles in the basal glandular cells transpose to the apex and are expelled into the glandular lumen. The stromal cells subsequently flatten into a low cuboidal form. Stromal cell differentiation from reticular spindle-shaped cells into plump predecidual cells and phagocytic granulated cells defines two layers in the functional endometrium known as the superficial compactum and the deeper spongiosum. The spongiosum has a loose edematous matrix that is the consequence of increased capillary permeability, mediated possibly by prostaglandins. The predecidual, late secretory phase stromal cells produce several metabolically active substances, as previously described, and are infiltrated by migratory leukocytes. The release of lysosomal enzymes from endometrial cells and possibly also from leukocytes may be involved in the initiation of menstruation.
Menstruation
Menstruation is controlled by many complex, interrelated, and incompletely understood factors. Normal menstruation results from progesterone withdrawal from the estrogen-primed endometrium. Changes that occur in the endometrium during menstruation were described by Markee by observation of endometrial tissue transplanted to the anterior chamber of the eyes of rhesus monkeys. Markee described cyclic changes in endometrial vascularity and the development of coiled vessels supplying the superficial two thirds of the endometrium. The estrogen-primed endometrium of the follicular phase is compact, with relatively underdeveloped vasculature. Progesterone converts this endometrium into a thick, edematous, secretory lining that is glycogen enriched and prepares the metabolically active stroma and glands with an increased vasculature to receive and nourish a fertilized ovum. If implantation does not occur, estrogen and progesterone levels fall, prostaglandin synthesis occurs, and lysosomal membranes rupture, causing constriction of the spiral arterioles, ischemic necrosis, and sloughing of the endometrium superficial to the basalis layer.
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