From menarche to menopause, hormones affect women’s lives. In many cultures there are mysteries surrounding the role of hormones as well as the physiologic events, such as menstruation, that occur as a result of hormonal action. Fortunately, researchers have cleared up many of the mysteries surrounding hormones and the role they play in our bodies. This research has led to increased understanding, acceptance, and improved treatment modalities for various conditions occurring as a result of hormonal dysfunction.

An understanding of the physiology of menstruation is crucial because it is the basis for understanding normal and abnormal variations. Chapter 1 begins with a discussion of the historical and cultural aspects of menstruation. It concludes with a review of normal anatomy and physiology of menstruation and the role of hormones in menstruation and reproduction.

Problems associated with menstrual periods such as dysfunctional bleeding, premenstrual syndrome, and dysmenorrhea account for many of the visits women make to health care providers. In Chapter 2 the origin of these problems and treatment modalities will be discussed.

Many forms of contraception are available. Hormones play a role in most methods, and the mechanism of their action in preventing conception will be discussed in detail in Chapter 3. While contraceptive needs change during a woman’s life span, there are options for every age and preference. Additional new methods for contraception have recently been approved and released for use in the United States and even more are in the testing phase. These new methods as well as the risks, benefits, and management of older, more traditional methods of hormonal contraception will be discussed.

Menopause is not a disease but rather a normal consequence of aging. As our population ages, questions concerning menopause and the role of hormones in the management of menopause abound. Whether to use hormone therapy is a widely discussed and often controversial topic and one that will be considered in detail in Chapter 4. Recent research studies have attempted to clarify the risks and benefits of hormonal replacement after menopause, but the results are confusing. The implications of these studies will be discussed and clarified so that you can provide up-to-date information to your patients.

Nursing is a field predominantly comprised of women—no wonder questions about the role of hormones in normal and abnormal menstrual function, contraception, and menopause are frequently directed to nurses. This is an excellent opportunity for nurses to educate the public and provide women with valuable information that may improve their quality of life. The goal of this continuing education course is to help you, the nurse, be informed and educated so that you can continue to provide honest and accurate information to your patients.

Chapter 1: Menstruation

Nearly every woman can reflect back to the time when she learned of menstruation. For many, it was a mysterious event surrounded by old wives tales. For others, information was gathered from health classes or well-informed mothers, teachers, or health professionals. Some were not prepared and were surprised and frightened. To be sure, menstruation is surrounded by taboos, superstitions, and myths even today. While attitudes toward menstruation vary among cultures and among women, it is helpful to gain a historical perspective. This information is limited, but there are references to menstruation dating back to Biblical times.

From an evolutionary perspective, menstruation occurred in only a few species such as anthropoid apes, old world monkeys, and humans.¹ The word “menstrual” has its origin in the Latin word for “moon” or “month.” At some point, menstruation became a monthly or lunar event. The evolution of this event is not widely understood though it may be related to primitive humans hunting by the light of the moon and thereby causing cycles to occur at monthly intervals. It is further speculated that because there was inadequate light for hunting during the new moon phase, ovulation may have typically occurred at that time to permit the procreation of the species. From a physiological perspective, it may simply be a connection between the visual cortex and the hypothalamus.¹ Since the menstrual cycle begins with the influence of hormones produced in the hypothalamus, it is theorized that communication between the visual cortex and the hypothalamus results in regulation of cycle length. This theory is proven in sheep, whose cycle length is controlled by the length of day. In humans it is not uncommon for women who are working or living together to have similar cycles.

Cultural, historical attitudes

Many myths and taboos surround menstruation in various cultures. The word “taboo” is derived from a Polynesian word “tabu,” which originally meant “menstruation.”¹ In many cultures menstruation was seen as unclean. Some cultures had strict rules such as requiring cleansing baths after menstruation, while others had rules mandating segregation of women during menstruation. In Middle East cultures, women sometimes left home or lived in special huts during the monthly cycle. Even if allowed to live at home, these women were not allowed to prepare food, visit a sick relative, or touch their husbands during menstruation.¹ Many of these attitudes continue today.

In the Western world, rules concerning the management of the monthly cycle and menstrual blood can be traced to Biblical times. In Leviticus 15, rules of hygiene for women during the monthly cycle are discussed.¹ A woman with a discharge of blood was considered impure for seven days, and anyone who touched her was considered to be unclean “until evening.” Additionally, everything that she touched or sat upon during this time was considered impure.¹

Roman attitudes concerning menstruation can be traced back to 1 AD.¹ Menstruation that occurred at the time of a lunar or solar eclipse was thought to cause irreversible evils. Contact with menstrual blood was thought to turn wine sour and cause crops to be barren and garden seeds to dry up.  A more positive belief was that menstrual blood exposed to flashes of lightning caused the storms to disappear, and there were medicinal uses in which the blood was used to make liniments and to treat abscesses and boils.¹

In Europe, the Medieval church prohibited a menstruating woman from entering a church and also forbade intercourse during that time. Others believed that menstruation was a curse that occurred as a result of Eve’s fall into sin as described in the Bible.¹

Knowledge about menstruation has increased significantly, and attitudes have changed. Approximately three centuries ago it was found that oophorectomy (removal of the ovaries) resulted in cessation of menstruation. Beginning in the 19th century, more sophisticated scientific investigation was conducted. It was at this time that an attitude concerning the frailty of women, especially during menses, was promoted.¹

Finally, during the 20th century the physiology of menstruation was investigated more thoroughly. At that time scientists isolated estrogen, progesterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), and prostaglandin.¹ While scientific research has led to a greater understanding of menstrual function, many disorders associated with menstruation persist and will benefit from further investigation.¹

Attitudes toward women changed greatly during the 20th century. Perhaps the biggest change in attitude toward menstruation occurred as a result of the feminist movement of the 1960s and 1970s. Those decades saw a change in attitudes and cultural influences as the Women’s Liberation Movement gained popularity. Books such as Germaine Greer’s The Female Eunuch (1970) helped to advance this cause. Attitudes toward menstruation changed significantly, and what was once discussed only behind closed doors now was discussed openly.

Female reproductive organs

The uterus, the ovaries, the fallopian tubes, and the vagina are the female organs of reproduction. (See Figure 1.) A review of these organs and their function will aid in understanding the role of hormones and the menstrual cycle.

Figure 1 - Female Reproductive Organs

SOURCE: Courtesy of Solvay Pharmaceuticals Inc. Permission granted.

Ovaries

The ovaries are the female gonads or sex glands. They are two small almond-shaped organs located on either side of the uterus. At birth each ovary contains about 1 million eggs. This number decreases to about 400,000 at puberty, but during a woman’s average reproductive life, only about 400 mature enough to be fertilized. The development and release of the ovum (egg) and the secretion of the hormones estrogen and progesterone are the two primary functions of the ovary.²

Fallopian tubes

The fallopian tubes are long, slender tubes approximately 4 inches long that extend from either side of the uterus, one to each ovary. Fimbriae are small fingerlike extensions that extend from the ends of the tubes. Their movements sweep ovum from the ovaries into the tubes in preparation for fertilization, which occurs in the distal portion of the tube. After fertilization it takes about five days for the ovum to travel to the uterus.²

Uterus

The uterus is a hollow pear-shaped muscular organ that lies between the bladder and the rectum. In the non-pregnant state, it is about 1 inch thick, 2 inches wide, and 3 inches long and weighs about 2.5 ounces. During pregnancy it enlarges to weigh about 2 pounds. The uterus has three layers: the perimetrium, the outer layer; the myometrium, the middle and muscular layer; and the endometrium, the inner mucous membrane layer.  The role of the uterus is

1. menstruation, in which the endometrial tissue is expelled;
2. support for the fetus, allowing it to grow during pregnancy; and
3. contractions that expel the fetus during labor and birth.²

Vagina

The vagina is a tube leading from the uterus to the outside. It is primarily comprised of muscle, connective tissue, and mucous membrane. It functions as a canal for the passage of menstrual blood and uterine secretions, as the female organ of sexual intercourse, and as the birth canal.

The ovaries, fallopian tubes, uterus, and vagina are important in the function of the normal menstrual cycle, but their function is made possible by the action of hormones initiated by the hypothalamus and the pituitary gland.²

Puberty

Before the normal menstrual cycle occurs, a series of maturational events must take place. Puberty is the term that describes these events. It is the period of life in which both sexes become capable of reproduction. In females, it begins with an accelerated period of growth followed by breast development and axillary and pubic hair growth, and ends with menarche (onset of menstruation).

The sequence of events in puberty lasts an average of 4.5 years and is influenced by a number of factors. On average, puberty begins at 9.8 years. Menarche occurs at a mean age of 12.8 years. Genetics is the most important factor in determining the age at which puberty begins, but geographic location, nutrition, weight, general health, nutrition, and psychological factors are also important. In general there is a fairly strong correlation in ages at the time of puberty between mothers and daughters, as well as between sisters.² 

The menstrual cycle

Menstruation is the normal, predictable physiological process whereby the inner lining of the uterus is expelled by the body.  Typically, this occurs monthly. The onset of the menstrual period is referred to as menarche and signals the beginning of a woman’s reproductive life. Menstruation ceases at the time of menopause, which signals the end of reproductive function.²

Hormones

Hormones are chemical substances that travel from a special tissue, where they are released into the bloodstream, to distant responsive cells, where the hormone exerts its characteristic effects.³ Hormones secreted by the hypothalamus, pituitary, and ovary must work together in order for normal menstrual function to occur.

Hypothalamic-pituitary-gonadal axis

The hypothalamus is located at the base of the brain and near the pituitary gland. It secretes gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The production of FSH and LH by the anterior pituitary regulates the production of estrogen and progesterone by the ovary. This action is referred to as the hypothalamic-pituitary-gonadal axis and forms the basis for understanding normal menstrual function.  Figure 2 depicts the mechanism of the hypothalamic-pituitary-gonadal axis.⁴

Figure 2 - Hypothalamic-pituitary-gonadal axis

When discussing normal menstrual function, it is helpful to consider the changes that occur simultaneously in the ovary and the uterus (endometrium). In this pattern of events, the ovarian follicle matures at the same time the endometrium is developed within the uterus.

Ovarian cycle

The development of the ovarian follicle is crucial to normal menstrual function, and therefore the ovarian cycle will be discussed first. In a typical cycle, there are two phases, the follicular, and the luteal phase, which constitute the ovarian cycle. 

Follicular phase

The follicular phase occurs days 1-14 in a 28-day cycle. It is called the follicular phase because it describes the development of the ovarian follicle. The production of FSH and LH by the anterior pituitary stimulates the primordial (primitive) ovarian follicle to grow and mature. As it matures, the cells produce a fluid that is high in estrogen. Maturity continues, and the follicle moves toward the surface of the ovary, where it is then termed a graafian follicle. A surge of LH 24-36 hours before ovulation results in production of androgens by the ovarian cells. Androgens enhance sex drive at the time of increased fertility and also work to continue the degeneration of the less dominant follicles. LH also stimulates the ovary to produce progesterone, which helps stimulate the pituitary to produce FSH, which ensures that the dominant follicle is allowed to mature. Higher levels of progesterone increase the distensibility of the follicular wall and aid in the release of the ovum. Ovulation is now complete. Typically, this process occurs on Day 14 of a 28-day cycle. The ova are fertile for only about 24 hours after ovulation, making the timing of intercourse critical if fertilization is to occur. The LH surge is the most accurate prediction of impending ovulation and is the basis for ovulation predictor kits. As noted, the LH surge is detectable 24-36 hours before ovulation and usually lasts for 48 to 50 hours.^2,3,5

Luteal phase

The luteal phase typically occurs Day 15 through Day 28 of a 28-day cycle. Once ovulation has occurred, the cells of the empty follicle form a cystic mass on the ovary called a corpus luteum.

The corpus luteum is important because it produces small amount of estrogen and progesterone, which help stabilize the lining of the uterus and prepare it to receive the fertilized ovum. If fertilization does not occur, the corpus luteum deteriorates in response to falling levels of estrogen and progesterone. These decreased levels of estrogen and progesterone can no longer support the endometrium of the uterus and lead to menstruation. If fertilization occurs, the corpus luteum is prolonged by the development of human chorionic gonadotropins produced by the embryo. The HCG maintains steroidogenesis until about nine or 10 weeks, at which time this vital function is controlled by the placenta.^2,3,5

Endometrial cycle

The endometrial or uterine cycle can be divided in four phases: the menstrual, proliferative, secretory, and ischemic. The first day of menstrual bleeding is the beginning of the menstrual phase and occurs in response to cyclic hormonal changes that occur when the ovum is not fertilized. Estrogen levels are very low during this part of the cycle. Endometrial cells that developed during the previous cycle are sloughed off and shed through this process. While these cells, tissue, and mucus are shed, the basal layer of the endometrium is regenerating, and new cell growth begins. This phase usually occurs about 14 days after ovulation and lasts three to five days in a 28-day cycle. Menstrual flow usually results in a blood loss of 20-60 ml and 13 mg of iron,⁶ and varies among women.

The proliferative phase is marked by an increase in levels of estrogen, which stimulate and increase the lining of the endometrium. In the early stages of this phase, the endometrium is 1-2 mm thick, but at the end of this stage, immediately before ovulation, it increases to a thickness of 8-10 mm. Cervical mucus becomes thin, clear, stretchy, and more alkaline, making it more favorable to sperm and enhancing the opportunity for fertilization to occur. This phase coincides with the follicular phase of the ovarian cycle.^2,3

The secretory phase is dominated by progesterone released by the corpus luteum after ovulation. Progesterone secretion increases the vascularity of the endometrium, causing it to become thicker and ready to nourish the fertilized ovum. This phase typically lasts from Day 14 to Day 25 and predominantly coincides with the luteal phase of the ovarian cycle.^2,3

When fertilization and implantation do not occur, the corpus luteum begins to degenerate and results in a fall of estrogen and progesterone. No longer receiving support of these hormones, the endometrial circulation decreases, causing blood vessels to constrict and necrose. Subsequent sloughing of these layers of endometrial tissue marks the start of the next menstrual phase. ^2,3,4

Figure 3 - The Menstrual Cycle

SOURCE: Cohen, S.M., Kenner, C.A., & Hollingsworth, A.O. (1991). Maternal, Neonatal, and Women's Health Nursing. Springhouse Corp. Used with permission.

Conclusion

Normal menstrual function is a complex series of events. Cycle length in a healthy woman is generally thought to be 28 days, but that length may vary from 21 to 35 days and still be considered normal. Bleeding typically lasts for three to seven days with a normal preovulatory phase, which can range from nine to 23 days, and a postovulatory phase ranging eight to 17 days. The cycle length is determined by the rate and quality of follicular development and can be affected by other factors. Understanding basic menstrual function will aid in the understanding of hormones and the disruptions that may occur.³ 

Chapter 2: Common Disturbances Of Menstrual Function

The onset of menstruation, or menarche, is a predictable event in the adolescent, typically occurring 2 to 2.5 years after breast budding and about 1 year after the growth spurt. In the U.S., this usually occurs at about 12.8 years of age but can occur as early as 9 and as late as 16. Many adolescent girls do not have regular monthly menstrual cycles during the first year or two after menarche, but usually establish normal ovulatory cycles resulting in regular menstrual cycles within two years of the first menstrual cycle. Few adolescents fail to achieve menarche by age 16.¹

Amenorrhea

Definition

Amenorrhea is the term used to describe the absence of menstruation and is the first topic to be discussed as a disturbance of menstrual function. Amenorrhea is further defined as primary and secondary:²

Primary amenorrhea implies that menses never began. Secondary amenorrhea is amenorrhea that occurred at some time after the establishment of normal menstrual function.³

Some examples:

• No menses by age 14 with the absence of growth or development of secondary sex characteristics (primary amenorrhea).
• No menses by age 16 regardless of the presence of growth or development of secondary sex characteristics (primary amenorrhea).
• No menses for a length of time equal to a total of three of the previous cycles or six months of amenorrhea (secondary amenorrhea).

Evaluation and treatment

Evaluation and treatment are improved when amenorrhea is systematically evaluated so that important information is not overlooked. Figure 4 represents the physiology of menstruation related to the diagnosis of amenorrhea.

Figure 4 - Diagnosing the Cause of Amenorrhea

The first step in evaluating the cause of amenorrhea is to obtain a complete history.  In the process, symptoms of psychological or emotional stress, family history, nutritional status, weight loss, and obvious signs of abnormal growth and development should be assessed.⁴ Signs of developmental abnormalities such as those found in Turner’s syndrome will most likely be found during this initial evaluation, when questions concerning growth and development are asked.³ In these patients, further evaluation and treatment should be referred to a geneticist or endocrinologist and are beyond the scope of this article.

In all cases of amenorrhea, the possibility of pregnancy should be determined by laboratory testing. Once pregnancy has been excluded, further testing can be performed. A physical exam should be performed to determine that the vagina is patent and there is continuity between the vaginal orifice, the vaginal canal, and the endocervical canal. 

Laboratory studies are an important part of the initial evaluation of amenorrhea. After the physical exam is complete, further diagnostic evaluation can be ordered. Nurses can expect blood studies including a TSH and prolactin level to be ordered. The TSH level will eliminate the presence of hypothyroidism. While it is unlikely that hypothyroidism is the cause of amenorrhea, it is relatively easy to diagnose and correct. Therefore, it is considered an important component of laboratory evaluation. If hypothyroidism is the cause, normal menstrual periods will likely occur once the condition is corrected.³

Some patients who have amenorrhea also have the presence of galactorrhea (breast milk unrelated to lactation). This information may be pertinent to the history and diagnostic evaluation of amenorrhea. A prolactin level will help to determine the cause of galactorrhea and is usually included in the initial laboratory testing.² The relationship of galactorrhea to amenorrhea will be discussed in more detail later.

In summary, testing that nurses can expect to be ordered initially includes urine or serum pregnancy test, TSH, and prolactin level. Laboratory tests are generally followed by a progesterone challenge. In the progesterone challenge, the patient is given progesterone parenterally or orally. In the oral administration route, medroxyprogesterone acetate or micronized progesterone is used.^3,5,6 Progesterone in oil may also be given parentally. Generally, bleeding will occur within about 10 days of completion of the medication. The presence of bleeding will confirm that there are no obstructions in the cervix or vagina prohibiting menstruation. Bleeding will also confirm that there are adequate levels of estrogen present to build the endometrial lining. Bleeding after the progesterone challenge often confirms that the cause of amenorrhea is anovulation (failure to ovulate).¹

Failure of the progesterone challenge to produce withdrawal bleeding can be caused by a number of problems:  A rare condition called Asherman’s syndrome is the presence of intrauterine adhesions that typically occur after dilatation and curretage surgery.  A D&C is performed following spontaneous or elective abortions and other problems related to heavy bleeding of the uterus. Amenorrhea can also be caused by ovarian failure or testicular feminization, a condition in which patients have a 46XY karyotype but are phenotypically female.³ The gonads are testicles, usually located in the abdomen.⁷ Therefore, if withdrawal bleeding does not occur after the progesterone challenge test, further diagnostic testing is required.

At this point testing will likely progress to the evaluation of ovarian function. Ovarian dysfunction represents one of the most common causes of amenorrhea. A simple assay of the FSH and LH will determine if the failure to produce bleeding after the progesterone challenge is due to ovarian dysfunction such as menopause or if further testing into other causes should be pursued.

FSH levels in the normal adult female generally range from 5-30 IU/L with normal LH levels between 5-20 IU/L. Prepubertal and hypothalamic and pituitary dysfunction levels of FSH and LH are less than 5 IU/L, while ovarian failure or hypergonadotropic levels such as those found in the postmenopausal state are generally greater than 30 IU/L in both the FSH and LH assays. Results of these tests often indicate that the clinician needs to pursue further testing, such as chromosomal analysis. The presence of Turner’s syndrome and other chromosomal abnormalities as a cause of amenorrhea will be confirmed by the chromosomal analysis.³

Recall that initial assessment included determining the presence of galactorrhea as well as a laboratory assessment of the prolactin level. In women with amenorrhea and galactorrhea, the presence of a pituitary tumor may be suspected. Improvements in diagnostic modalities have led to increased diagnosis of this condition as a relatively common cause of amenorrhea. Prolactin level less than 20ng/ml are generally considered to be normal. Prolactin levels greater than 100ng/ml represent a need for a more aggressive approach and nearly always suggest the presence of a prolactin-secreting adenoma tumor. The presence of these tumors is confirmed by a coned down view of the sella turcica through computerized tomography (CT) scan with contrast enhancement or by magnetic resonance imaging (MRI). Prolactin-secreting adenomas are common, and while they sound serious, they are rarely malignant. Aside from galactorrhea and amenorrhea, there are rarely any other symptoms. If less than 10mm in diameter, the tumors do not require surgery and are referred to as microadenomas. They are often treated with bromocriptine for patients wishing to conceive or those bothered by galactorrhea. Prolactin levels should be followed annually, and periodic repeat CT or MRI scans should be done.³

Tumors larger than 10mm in diameter often are detected as a result of other symptoms such as headaches and visual disturbances, and often require surgery as well as radiation therapy. Medical therapy is rarely helpful.³

Patients who have low or normal FSH and LH levels and normal prolactin levels, yet fail to have normal withdrawal bleeding can be classified as having hypothalamic amenorrhea, a disturbance in the central nervous system. There is often an association with a stressful situation, but it may also be related to weight loss, exercise, or anorexia nervosa. Use of medications such as antipsychotics or heroin/methadone use may also cause amenorrhea. If not currently interested in becoming pregnant, these women may use oral contraceptives, which may induce monthly menstrual cycles while providing contraception.

Conclusion

Clinicians often encounter amenorrhea not associated with pregnancy. Amenorrhea causes worry and anxiety, but it can be easily managed when evaluation is done systematically. Understanding the basic physiology of menstruation and the role of hormones in menstruation aids in the understanding of causes of amenorrhea. Women who experience amenorrhea unrelated to pregnancy should be reassured that in most cases the cause can be identified and treatment initiated based on the cause.

Dysfunctional uterine bleeding

Dysfunctional (abnormal) uterine bleeding is a common occurrence. Beginning in adolescence, women are taught that their periods are supposed to occur at 28-day intervals with little change in the amount or duration of bleeding. The fact of the matter is that menstrual cycles do vary somewhat among women in interval, duration, and the amount of bleeding, but they usually do not vary significantly in the individual.⁸ Diagnosis of dysfunctional uterine bleeding can pose many problems for clinicians because there are so many factors that can cause the irregular bleeding. Several terms are used to describe dysfunctional uterine bleeding. The most common forms of dysfunctional uterine bleeding and basic definitions are.^3,8

• Amenorrhea—No menses for a length of time equal to a total of three of the previous cycles or six months of amenorrhea.
• Oligomenorrhea—Cycle interval longer than 35 days.
• Polymenorrhea—Cycle intervals less than 21 days.
• Menorrhagia—Regular cycle intervals, excessive flow and duration.
• Menometrorrhagia—Increased flow or duration of flow occurring at irregular intervals.
• Postmenopausal bleeding—Spotting or any bleeding more than 12 months after the last menstrual period.

Pathophysiology of menstrual cycle

Menstruation results with the withdrawal of estrogen and progesterone. When there is no implantation of a fertilized ovum, there is demise of the corpus luteum and the hormonal support of the endometrium is withdrawn. This lack of hormonal support results in a decrease in endometrial circulation, causing blood vessels to constrict and necrose. The ensuing sloughing of the endometrial tissues marks the beginning of menses.^3,8

The normal cycle interval is 21 to 35 days. On average, most women experience between 400 and 500 cycles between menarche and menopause. Normally, 20 to 60ml of blood is lost during each cycle. Normal iron loss during each menstrual cycle is 13mg.⁸ Iron deficiency anemia results when the blood loss exceeds 60ml, and while not life-threatening, it can adversely affect the immune system and quality of life.^2,9-11

Excessive menstrual bleeding is one of the most common reasons women seek medical care. Yet quantifying the amount of blood loss poses a challenge to clinicians. We have learned that a loss of 60ml of blood represents excess, but how does the patient accurately measure that? In fact, research has shown that when the actual amount of blood loss has been accurately quantified using reliable laboratory measures, only about 38 percent to 76 percent of women who had complained of heavy bleeding actually had menorrhagia or excessive bleeding.³ Several methods of determining the amount of blood loss have been used, yet most are fraught with inaccuracy.^2,8,9

Self-reports of menstrual blood loss

In the self-report method, the woman subjectively quantifies the amount of blood that has been lost during the menstrual period. Reports of both overestimation and underestimation abound. Therefore, this method of diagnosis is insufficient.³

Number of days of actual bleeding

Recording the number of days of actual bleeding has been used. Bleeding in excess of seven days, for example, has been diagnosed as menorrhagia. This has not been shown to be an accurate method of diagnosing menorrhagia as several studies have shown that the majority of blood is lost in the first two days of bleeding. While women who bleed more than seven days certainly may be at risk for menorrhagia, bleeding more than seven days is not diagnostic of menorrhagia. However, keeping track of the date, amount, and relationship to normal menstrual periods is important.⁹

Number of sanitary products

Use of sanitary products varies significantly among women. It is influenced by personal preferences, hygiene, and financial resources. Several studies dispute the reliability of counting the number of sanitary products to quantify blood loss. In one study, it was found that one woman used 40 pads to collect less than 80ml of blood in eight menstrual periods while another woman used 21 pads to collect 80ml in blood in 14 menstrual periods. Absorbency rates vary significantly among products, further limiting the reliability of this method.⁹

Weight of products

It has been suggested that weighing the sanitary product before and after use is an effective way to determine blood loss. While it would seem that this would be an accurate method of measurement, it assumes that menstrual fluid is entirely blood. It does not take into account other sources, such as endometrial tissue, vaginal secretions, and other fluids. In fact, the analysis of the menstrual fluid showed that blood accounted for only about 36 percent of the fluid.^8,9

Pictorial blood loss assessment chart

The most promising method of assessing menstrual blood loss is the pictorial blood loss assessment chart.³ In this method, women are asked to compare the extent to which their sanitary products (tampons or pads) are soiled with a chart, which shows light, moderate, and heavy saturation. They are asked to make this comparison each time they change their pad or tampon and to record their assessment on a tally sheet. Numerical scores are assigned as follows: For pads, a score of 1 indicates light staining, 5 for moderate staining, and 20 for complete staining. Tampons are assigned a score of 1 for light staining, 5 for moderate staining, and 10 for complete staining. Several studies have confirmed a high degree of sensitivity and specificity using this method. These studies help differentiate normal bleeding from menorrhagia and have been well accepted by women who used this method.⁹

Causes of dysfunctional bleeding

The cause of dysfunctional uterine bleeding is often difficult to diagnose. Often the cause is determined after excluding other possible causes. In general, the cause of dysfunctional bleeding can be divided into three categories: pregnancy-related causes, reproductive tract disorders, and systemic conditions. See Table 1 for a complete listing of these conditions.^2,8,9

Pregnancy should be eliminated as a cause of abnormal bleeding in any woman of reproductive age. Bleeding during pregnancy can occur for several reasons. These may include threatened, incomplete, or missed abortion; ectopic pregnancy; or retained products of conception. Trophoblastic disease—such as molar pregnancy—can also result in bleeding. Obvious complications of pregnancy such as placenta previa and placental abruption are excluded form this category.^8,9

There are many causes of abnormal bleeding associated with reproductive tract disorders. In one study, nearly 50 percent of those with menorrhagia were found to have fibroid tumors, while another 16 percent had uterine polyps. Fibroid tumors are common, found in approximately 30 percent of women.⁸ Adenomyosis, a benign condition of the uterus, can also contribute to abnormal bleeding.

Endometriosis, a condition that can only be definitely diagnosed laparoscopically, occurs when endometrial tissue implants itself outside the uterine cavity. It is theorized that this occurs due to retrograde menstruation. Instead of flowing through the cervix, menstruation backs up into the abdominal cavity. When the endometrial tissue implants bleed, they may cause irregular and/or heavy bleeding that is usually associated with pain.⁷

There are some cancerous conditions that can cause abnormal or dysfunctional uterine bleeding. These include vulvar, vaginal, cervical, ovarian, and uterine cancer.

Hyperplasia, a condition that can occur as a result of the use of unopposed estrogen during the menopause period, can result in heavy bleeding.

Infections such as cervicitis and endometritis can cause dysfunctional bleeding. Trauma to the vulva, vagina, or cervix is another potential cause of abnormal bleeding, as are the presence of IUDs and foreign bodies.^3,8,9

Liver disease can affect production of fibrin and other clotting factors, thereby increasing the occurrence of dysfunctional bleeding. Disorders of the endocrine system such as thyroid disease, adrenal disease, and pituitary disease (prolactinemia) may also cause dysfunctional bleeding.

Often, bleeding disorders such as von Willebrand’s disease are not diagnosed until adolescence, when heavy bleeding occurs at, or soon after, menarche. Other bleeding disorders such as idiopathic thrombocytopenia purpura (ITP), aplastic anemia, and leukemias may be diagnosed when a woman seeks treatment for dysfunctional uterine bleeding.

Several medications have been linked to abnormal bleeding. Prolonged use of progesterone-only contraceptives (Depo Provera and progesterone-only oral contraceptives) have been linked to dysfunctional bleeding. Other drugs implicated in abnormal bleeding patterns include digitalis, phenytoin, tranquilizers, and steroids.^3,8,9

Pathophysiology

Dysfunctional uterine bleeding typically occurs when there are alterations in hormonal patterns during the menstrual cycle. Most alterations occur as a result of disruption of hormones in any one of three categories related to estrogen withdrawal, estrogen breakthrough bleeding, or progestin breakthrough bleeding.

Estrogen withdrawal is often represented as midcycle bleeding and occurs when estrogen levels decrease before ovulation. This can occur as a result of medication use or other systemic conditions. Addition of exogenous estrogen either orally or parenterally often resolves the problem.

Estrogen breakthrough bleeding commonly occurs as a result of anovulatory cycles. When ovulation fails to occur and no corpus luteum develops, there is no progesterone produced, but estrogen continues to stimulate the development of the endometrium. The structure of the endometrium becomes unstable, and bleeding ensues. This type of dysfunctional bleeding pattern can also occur as a result of unopposed estrogen replacement therapy, a previously common practice in the treatment of vasomotor symptoms associated with menopause.

Progesterone breakthrough bleeding is often seen in women who have used long-term progestin therapy such as Depo Provera. High progestin to estrogen ratios cause the endometrium to become atrophic, resulting in irregular or abnormal bleeding. Like estrogen withdrawal bleeding, this type of bleeding responds well to the addition of supplemental estrogen therapy.

Evaluation

The initial evaluation of dysfunctional uterine bleeding should begin with a thorough history. This should include family history and past gynecologic, medical, and menstrual history. The pattern of bleeding should be evaluated carefully. Assessment includes the interval, duration, and amount of bleeding. Use of a calendar is helpful when trying to assess the bleeding pattern because it helps to show changes in the pattern of bleeding in relation to lifestyle events or changes. Pain in association with bleeding should be assessed, as should bleeding in other areas such as excessive bruising, epistaxis, or gingival bleeding. Diet, weight loss, and exercise may lend further clues to the origin of the symptoms.^8,9

A complete physical exam is critical to the evaluation process. This should include assessment of vital signs, palpation of thyroid, and observation for excessive bruising or evidence of trauma or abuse. A breast exam should also be conducted, and the patient should be asked about the presence of galactorrhea, which might indicate a pituitary disorder.^2,3,9,12

After the general physical exam, a complete pelvic exam should be performed. The external genitalia should be carefully inspected for ulcerations, lesions, or evidence of trauma. Presence of vaginal discharge may indicate an infection and should be evaluated. An inspection of the cervix can confirm the presence of lesions, polyps, or cervicitis that can cause dysfunctional bleeding. Often fibroid tumors can be detected during the bimanual exam and then later confirmed by ultrasound exam. Tenderness that occurs when the cervix is gently moved can point to an infection. A Pap smear should be performed if one has not recently been performed, and cultures to rule out chlamydia and gonorrhea may also be helpful.^2,3,9,12

Laboratory tests can add specific information about the cause and severity of the bleeding. Initially, a pregnancy test should be done on all women of reproductive age to eliminate threatened, missed, or incomplete abortion or ectopic pregnancy. A complete blood count (CBC) should be done, including a platelet count. A mean corpuscular volume (MCV) of less than 80 indicates the presence of microcytic anemia. When resources are limited or the need is emergent, hemoglobin and hematocrit levels can be done in most offices and will determine whether the bleeding is resulting in anemia. If the tests confirm anemia, serum iron or serum ferritin levels to assess iron stores will be helpful. If coagulation disorders are suspected, platelet count, bleeding time, prothrombin time, and activated partial thromoboplastin time are helpful. A thyroid-stimulating hormone level (TSH) should be checked in patients who have symptoms suggestive of hypothyroidism. If anovulation is suspected, a serum progesterone level done on about cycle Day 23 will confirm whether ovulation has occurred. Liver function and renal function tests should be assessed if liver or renal disease is suspected. Laboratory tests are valuable tools, but they should be tailored to each woman’s symptoms so that valuable resources and health care dollars are not used irresponsibly.^2,3,9,12

Pelvic ultrasound is valuable in the assessment of dysfunctional bleeding, and nurses might expect and prepare the patient for this possibility. The nurse should reassure the patient that this is not a painful procedure. The transvaginal route, which uses a small vaginal probe, often provides the best information. With transvaginal sonography, fibroid tumors, an enlarged uterus, and pelvic masses are easily detected. Endometrial thickness can be measured as a method of evaluating the uterine cavity and can provide valuable clues about the cause of bleeding. Measurement of the endometrial thickness has limited value in the premenopausal woman, but is very relevant in the postmenopausal woman if hyperplasia is suspected. If polyps are suspected, saline infusion sonohysterogram can be performed to confirm the presence and location of the polyps. In this exam, a small amount of saline is injected into the endometrial cavity to provide contrast and to distend the uterus, which helps to detect the presence of the suspected polyps. On occasion, a hysterosalpingogram is necessary. While this test is usually indicated for the infertile patient to determine the patency of the fallopian tubes, the injection of contrast dye into the uterine cavity will help to detect uterine anamolies.^8,9,12

Assessment of the endometrial tissue provides further information about the cause of dysfunctional bleeding. Previously, dilation and curettage (D&C) was the gold standard for the evaluation of endometrial tissue. However, the development of a small (about 3 mm diameter) plastic pipelle catheter that is inserted through the cervix and into the uterus permits the withdrawal of endometrial tissue through negative suction. This procedure has replaced the D&C as the gold standard. The procedure can be done in the clinician’s office and has been found to be as effective as a D&C without requiring hospitalization or anesthesia. It is less expensive, as well. Nurses should expect this test to be performed and should prepare the patient for the possibility. Patients should be informed that there might be discomfort associated with the test. Pre-medication with a non-steroidal anti-inflammatory drug such as ibuprofen or naproxen will minimize discomfort. The endometrial biopsy can be very diagnostic because it provides specific information about the stage of the menstrual cycle as well as detecting abnormal tissue, such as that found in endometrial cancer or hyperplasia. Some experts believe that the endometrial biopsy should be considered for patients who experience dysfunctional bleeding beginning at age 35 or 40. Patients at risk for endometrial hyperplasia—such as menopausal women who have been on unopposed estrogen therapy, obese women, and those with hypertension and diabetes—are also candidates for endometrial biopsy.^3,8,12,13

Treatment

Because several factors can lead to the diagnosis of dysfunctional uterine bleeding, treatment should be individualized to the patient and to the cause. Initially, the treatment should be aimed at stopping the bleeding and correcting any anemia that may have occurred. After the cause of the bleeding is determined, treatment should be based on the diagnosis and prevention of recurrence.⁸ Several forms of treatment are available for the management of dysfunctional uterine bleeding. 

Nonhormonal treatment

Prostaglandin synthetase inhibitors (PSIs), also known as non-steroidal anti-inflammatory drugs (NSAIDs), are the most common non-hormonal methods of treating dysfunctional bleeding. These medications alter the synthesis of prostaglandins in the endometrium as well as altering the platelet aggregating and platelet aggregating inhibiting factors. While not all women with dysfunctional uterine bleeding will benefit from PSIs, they are especially useful in the treatment of menorrhagia. Women who have used PSIs have reported a 20 to 50 percent decrease in bleeding. The advantage to these drugs is that they are easy to obtain (most women have them in the medicine cabinet), affordable, and easy to take and have few side effects.  Another benefit of NSAIDs is that they moderate other symptoms of menstruation such as menstrual headache and dysmenorrhea. Side effects are usually minimal, but include nausea and vomiting, diarrhea, headaches, and possible gastritis. Table 2 indicates medications and dosages.^2,8-12

Hormonal therapies

Very heavy uterine bleeding may be treated with high doses of estrogen administered intravenously. The treatment allows rapid regrowth of the endometrium as well as increasing fibrinogen and factors V and IX, and promotes aggregation of platelets and clotting at the capillary level. Given IV, the dose is 25 mg Q4H until the bleeding stops. Estrogen can also be administered orally as: conjugated estrogen 1.25 mg or estradiol 2 mg Q4H for 24 hours, then daily for seven to 10 days.⁷

Oral contraceptive pills are the most common hormonal therapy for treating dysfunctional bleeding. Their use in reducing menstrual flow is well documented. Oral contraceptives cause endometrial atrophy, which leads to decreased menstrual blood loss. They also reduce prostaglandin synthesis as well as influencing coagulation and fibrinolysis. Oral contraceptives are a good choice for women who also desire contraception, and in the absence of contraindications, they are one of the most common therapies. Disadvantages include the side effects associated with oral contraceptives such as nausea and breakthrough bleeding, plus the need to take the medication daily.^2-7,9

Another common method of hormonal treatment of chronic dysfunctional bleeding is the use of progestins. A common indication arises in the woman who is chronically anovulatory who experiences very light or no menstrual bleeding followed by occasional episodes of heavy bleeding. Progestins can initially decrease the amount of bleeding and with continued use can regulate cycles and prevent recurrent heavy bleeding. Systemic progestins work by controlling endometrial proliferation and causing a more organized sloughing of the endometrial tissue. Progestins are usually administered in the latter half of the menstrual cycle, typically beginning on Day 15 and continuing through Day 25. Medications include medroxyprogesterone acetate, 10 mg per day, or norethindrone acetate 5 mg BID for 10 days. The disadvantages of cyclic progestins include bloating, nausea, weight gain, mood changes, and the need to use a calendar for scheduling use of the medication.^2,3,9,10,13

Intrauterine devices (IUDs) containing progestins (progesterone or levonorgestrel) are good options for treating dysfunctional bleeding, especially in women with chronic illness.⁷ The progestins are released directly against the endometrium, resulting in a significant decrease in blood loss. Mirena, a levonorgestrel-releasing IUD, has been approved by the FDA for use in the United States as a method of contraception. Its use in treating menorrhagia has been reported in the New Zealand Medical Journal.² A 94 percent reduction in blood loss over 12 months use was reported, with side effects include cramping and intermenstrual bleeding. Mirena may be somewhat more expensive than other methods of treatment, and it may not be covered by health insurance. The use of Mirena for dysfunctional bleeding has not been well studied in this country, and it should be limited to patients who desire contraception who also may suffer from dysfunctional bleeding.^2,3

Additional, but less popular, methods of treatment include the use of Danazol, a synthetic steroid, and gonadotropin releasing hormone (GnRH) agonists, which causes endometrial atrophy and may result in decreased bleeding, especially in patients with menorrhagia. Their side effects include hot flashes, acne, and decreased libido. These drugs are also rather expensive, and when combined with the unpleasant side effects, they are not well accepted and therefore limited to more severe cases in which surgical therapies are not acceptable.^{2,3, 8-13}

Surgical therapies

Surgical therapies render definitive treatment of dysfunctional uterine bleeding. The most common procedures are hysterectomy (complete or partial) or destruction of the endometrium by a procedure called ablation. In years past, D&C was the first choice for surgical therapy for diagnosis and treatment of dysfunctional uterine bleeding; however, clinical trials have failed to support D&C as a method of treatment. The procedure does have limited diagnostic value and is often used when office endometrial biopsy cannot be accomplished and sonography suggests pathology.^2,9,11

Hysterectomy can include removal of only the uterus (partial), or it can include removal of the uterus, fallopian tubes, and ovaries (complete). Either procedure can be done vaginally or abdominally, though complete hysterectomy is more often done through the abdominal approach. A hysterectomy is a definitive cure for dysfunctional bleeding and is certainly a reasonable option in cases in which there is other pathology. It also resolves many other problems including eliminating dysmenorrhea, providing permanent sterilization, and reducing risks for various types of cancers, depending on the extent of hysterectomy performed. Hysterectomy also negates the need for progestin therapy when hormone replacement therapy is instituted and therefore eliminates the irregular bleeding that often occurs with combined hormone replacement therapy.^8,9

But hysterectomy is not without risk and morbidity, and its benefits should be weighed against those risks. Women should be fully informed of the risks and discuss them with the physician so they can make an informed decision about the procedure that is best suited. Additionally, complications such as infection, hemorrhage, pneumonia or atelectasis, cardiopulmonary arrest, or emboli may result. Thrombophlebitis, paralytic ileus, and injuries to the urogenital organs may occur, and the patient should discuss those risks with the surgeon before the procedure. Hysterectomy is a major procedure, requiring general or at least significant regional anesthesia. Anesthesia risk should also be discussed with both the surgeon and the anesthesiologist.^9,10

Immediately postoperatively there may be significant pain and fatigue associated with the procedure. Recovery after hysterectomy is often long, with the median time from surgery to returning to work being approximately six to 11 weeks. Hysterectomy is also expensive, in terms of the patient’s out-of-pocket expenses and costs incurred by insurance companies.^{2,3, 8-11}

Endometrial ablation is a procedure that involves the destruction of the endometrium. It can be done in several ways including cryosurgery, laser vaporization, roller ball electrode, resection, and heat destruction by thermal balloon. Ablation is especially well suited for menorrhagia, a common type of dysfunctional uterine bleeding. In some cases ablation can be performed under local anesthesia with sedation in an outpatient or day surgery setting.^2,3,8-11

This procedure is complex, requiring experience and skillful technique. Risks associated with endometrial ablation include trauma, perforation, hemorrhage, and injury to adjacent organs. It is, however, associated with shorter recovery time, decreased blood loss, and lower surgical and hospital expense than hysterectomy.^2,3,8-11

Women who undergo endometrial ablation are usually satisfied with the procedure and report decreased menstrual bleeding, normal bleeding, or amenorrhea. Unfortunately, this procedure is not viewed as a definitive cure for menorrhagia. In 10 to 15 percent of women, the menorrhagia will not be relieved and will require further treatment. One study showed that this rate might be as high as 40 percent.^2,3,8-11

Women who undergo endometrial ablation will still require progestins at menopause if they decide to use hormone replacement therapy. Women of childbearing age will require contraception because endometrial ablation will not result in sterility. The long-term effectiveness of endometrial ablation is still being evaluated, but its advantages make it another option for treatment of menorrhagia.^{2,3, 8-11}

Conclusion

Dysfunctional uterine bleeding is one of the most common reasons for gynecological visits and is a significant concern for all women. There are many types of dysfunctional bleeding, and many causes. Understanding the role of hormones during menstruation can make it easier to understand dysfunctional bleeding.

Premenstrual syndrome

One of the most common complaints of women in their reproductive years is premenstrual syndrome, or PMS. In fact, recent epidemiological surveys report that as many as 75 percent of women suffer symptoms of PMS.  The prevalence of this condition has led to the development of criteria that has been published in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) ^10,13 The research involved in developing these criteria ultimately led to this condition being termed premenstrual dysphoric disorder. Today, PMDD is the more common term for this condition.¹⁴

Although premenstrual complaints were first formally investigated in 1931, references to them to can be traced back to the Dark Ages.³ Despite the prevalence of PMDD, there have been few developments in the treatment of this disorder, which affects millions of women each month.³

Diagnosis

The timing of symptoms is crucial to the diagnosis of PMDD. Symptoms can be divided into affective (or cognitive) and physical. (See Table 3.) In previous chapters the phases of the menstrual cycle were discussed in detail. Recall that the ovarian cycle was divided into the follicular and luteal phase. In order to accurately diagnose PMDD, the symptoms must occur in the late luteal phase and resolve within a few days of the onset of menstrual bleeding.¹⁵

Diagnosis of PMDD cannot be made based on an initial physician visit. Rather, accurate diagnosis must be made based on the occurrence of the symptoms during the luteal phase over at least two cycles. Since there are no objective tests for the diagnosis of PMDD, three tools have been developed that allow a woman to chart and measure her symptoms: the Daily Record of Severity of Problems (DRSP), the Premenstrual Record of Impact and Severity of Menstruation (PRISM), and the Calendar of Premenstrual Experiences (COPE). All are in a calendar format, allowing the woman to rate cognitive and physical symptoms, record medications used, and track menstrual bleeding. These have all been validated and used in clinical trials to demonstrate their effectiveness.¹⁶

In addition, a careful history should be obtained including family history and psychiatric history to eliminate the presence of an underlying psychiatric condition. Since the symptoms of PMDD can also be attributed to other physical causes, such as anemia and thyroid disorders, lab tests ruling out these causes should be performed.

For an official diagnosis of PMDD, the American Psychiatric Association criteria must be used. Prospective daily rating of these symptoms is crucial and the only accepted means of confirming the diagnosis.^15-17 (See Table 4.)

In conclusion, diagnosis of PMDD should be based on the above criteria determined from a charting of symptoms for at least two consecutive cycles. Symptoms must include at least one of the four core criteria (irritability, tension, dysphoria, and lability of mood) and at least five of the 11 total symptoms. Symptoms should be shown to interfere with usual activities. Finally, there should be clear evidence that most of the symptoms abate within a few days of the onset of bleeding.^16,17

Treatment

Treatment of PMDD can range from very conservative measures to those with pharmacologic interventions. For women who do not meet the above DSM-IV criteria completely, more conservative therapies are indicated, and, in fact, lifestyle changes are beneficial to most women.

Lifestyle changes

• Exercise:  Moderate, regular exercise has been shown to be effective. When exercise is combined with stress reduction therapies, symptoms are relieved even more effectively.
• Diet:  Decreasing the intake of caffeine, alcohol, and chocolate may be helpful. If there is swelling or edema, limiting the amount of salt may be of some benefit. Some improvement in symptoms was noted when meals were small, frequent, and consisted of complex carbohydrates, though these reports are anecdotal in origin. Use of a multi-vitamin preparation may also prove to be beneficial.

The changes described above have been shown to be beneficial to all women. Their effectiveness in treating PMDD is limited, but when used in conjunction with other conservative methods listed below, lifestyle changes do represent improvement when symptoms are mild.

Low-risk, evidence-based Treatments

The following therapies are low risk and have been shown to improve symptoms in evidence-based studies. All are available without prescription and are easily attainable. They have very few side effects, but attention must be paid to a calendar to ensure that they are used at the appropriate time.

• Vitamin B6:  Vitamin B6 has been shown to be somewhat effective in clinical trials. A dose of 100 mg daily is recommended during the last two weeks of the menstrual cycle. Note: Sensory neuropathy was reported in higher doses, and therefore dosages should not exceed this dosage.^10,12,14
• Calcium:  In clinical trials, women who took 1000 mg of calcium daily showed significant improvement in water retention, negative affective feelings, and pain during the premenstrual period.^15,16,18
• Magnesium: 360 mg of magnesium administered daily from Day 15 through the onset of menses showed significant improvement in menstrual pain and negative affective feelings.^10,12,14
• Vitamin E: In one randomized controlled trial, women with benign breast disease who complained of premenstrual breast pain were given Vitamin E daily. In addition to reduction of their breast pain, they also reported a decrease in physical symptoms and depression.^15,16,18
• Optivite: Optivite, a vitamin/mineral supplement, was also studied in randomized controlled clinical trials. Women who took up to six tablets daily during the luteal phase of the menstrual cycle reported a reduction in both physical symptoms and depression.^15,16

Pharmacotherapies

Women who fail to show improvement in symptoms after using the above therapies may be candidates for more intense treatment using prescriptive medications. These treatments range from NSAID regimens to psychotropic or hormonal regimens.

• Naproxen sodium: When taken seven days premenstrually, naproxen sodium (Anaprox) was found to improve premenstrual mood changes as well as menstrual migraines. Gastrointestinal side effects may occur.¹⁰
• Ponstel: Use of Ponstel (mefenamic acid) showed a decrease in physical and mood symptoms when compared with placebos.  Because it can cause gastric side effects, its use should be limited to seven to 10 days before menses.¹⁶
• Spironolactone: 100 mg of spironolactone (Aldactone) administered daily from Day 12 through the onset of menstrual bleeding was found to be effective in treatment of bloating and swelling. Because there is a potential for abuse and also because contraindications of potassium supplementation exist, this drug should be reserved for more severe cases.^15,16,18

Psychotropics

In severe cases of PMDD when lifestyle changes, low-risk treatments, and milder pharmacotherapies fail, psychotropic medications may need to be used judiciously. Until recently, there were few alternatives available, but thankfully, additional research has shown benefits to the use of psychotropic drugs.^15,18

• Selective serotonin reuptake inhibitors: This classification of drugs has been studied in detail and has been found to be effective in the management of severe PMDD. Fluoxetine (Prozac) was the most common choice and the drug that was studied in most clinical trials. As a marketing strategy to improve its acceptance as a treatment for PMDD, fluoxetine was renamed Serafem. Advertisements for Serafem appear on television and in women’s magazines. It was found to be effective at dosages of 20 mg/day throughout the menstrual cycle although it is also available in 10 mg/day doses. In one study, intermittent therapy using 10 mg or 20 mg/day during the seven to 14 days before the menstrual cycle was found to be beneficial. This is less expensive than continuous, daily use of fluoxetine, and because there was a reduction in overall side effects, intermittent therapy was found to be more acceptable to women. Side effects associated with fluoxetine include nausea, headache, insomnia, and diminished libido. In addition, Zoloft (sertraline hydrochloride), 50 to 150 mg/day, and Paxil (paroxetine hydrochloride), 10 to 30 mg/day, were found to be effective in relieving physical and psychological symptoms associated with PMDD. Adverse effects include headaches, nausea/gastrointestinal distress, sleep disturbances, and dry mouth.^15,16,18
• Anxiolytics: Several randomized controlled trials were conducted using Xanax (alprazolam) in dosing from 0.25 to 5.0 mg/day given seven to 14 days before menses.^10,14 The trials showed that this drug alleviated symptoms associated with PMDD. BuSpar (buspirone hydrochloride) has also been shown to be efficacious when administered in a daily dose of 25 mg/day for 12 days prior to menstruation. Adverse effects include concerns about dependence on the drug as well as concerns about withdrawal. The possible adverse effects of drug dependence and problems with withdrawal are a concern. Additional adverse effects include drowsiness and sedation.^7,16

Hormonal therapies

Various hormonal therapies have been studied in the treatment of PMDD. Some of these have shown promise while others are not as effective. Adverse effects and expense often limit the usefulness of these treatments.

• GnRH agonists: Lupron (leuprolide acetate) 3.75 mg/month was found to significantly reduce both physical and mood symptoms associated with PMDD. Another choice in this category is Zoladex (goserelin acetate)3.6 mg/month, which was found to alleviate physical symptoms, but did not effectively relieve mood symptoms. Because these drugs can mimic menopause and there are concerns about an increased risk of osteoporosis and cardiovascular disease, their use is not recommended for longer than six months.^15,16,18
• Danazol:  Classified as a synthetic androgen, Danazol (danocrine) suppresses the hypothalamic-pituitary-gonadal axis and effectively eliminates the midcycle surge of hormones. One study found that it was effective in the relief of mood symptoms and bloating. The dose used is 200 to 400 mg/day during symptoms. Side effects are those associated with use of androgens and include deepening of the voice, acne, bloating, and depression.^15,16
• Oral contraceptives: Studies so far have not shown that oral contraceptives are useful in treating PMDD.^15,16.18
• Progesterone: Progesterone alone has not been shown to be effective in treating PMDD.^15,16.18
• Estradiol: Transdermal estradiol (Vivelle, Climara, Estraderm) with a low-dose progestin (to prevent endometrial hyperplasia) administered from Day 17 through Day 26 has been proved effective in the treatment of PMDD.¹⁶

Conclusion

Women should be instructed to continue to chart their symptoms during treatment to help determine the effectiveness of the therapy. Assessment by the provider should continue every two weeks during the therapy to permit changes in dosages and treatment. PMDD is a condition with many symptoms, and it often requires more than one method of treatment. Therefore, the effectiveness of therapies may vary among women. Research on the treatment of PMDD is continuing.

Dysmenorrhea

Dysmenorrhea is one of the most common disturbances of the menstrual cycle, yet there are few studies available concerning the prevalence rates. One American study showed that up to 70 percent of university students considered their periods to be painful, while 60 percent considered their pain to be severe.¹⁹ This is comparable to a study of students in Sweden, in which the prevalence rate was found to be 72 percent.¹⁹

Dysmenorrhea is a common cause of absenteeism and certainly accounts for a diminished quality of life among many women. This is an important issue in women’s health, yet the majority of information available centers on the more global issue of chronic pelvic pain or more specific causes, such as endometriosis.¹⁹

Definition

Dysmenorrhea is defined as excessive pain or cramping in the lower abdomen during menstruation.¹⁵ Dysmenorrhea is divided into two types: primary and secondary. Primary dysmenorrhea refers to menstrual pain associated with ovulatory cycles and not associated with pathologic abnormality in the uterus, tubes, or ovaries. Secondary dysmenorrhea refers to menstrual pain associated with a variety of pathological conditions such as endometriosis, pelvic inflammatory disease, and adenomyosis.²⁰ A discussion of secondary dysmenorrhea is beyond the scope of this course.

Cause

Primary dysmenorrhea is caused by stimulation of uterine contractions by prostaglandin F2a. The amount of prostaglandin produced varies among women and therefore is the differentiating factor in severity of pain. Prostaglandin production is also known to cause side effects such as nausea, vomiting, headache, backache, and diarrhea, all of which are commonly reported during the menstrual cycle. Dysmenorrhea is usually associated with ovulatory cycles; therefore, primary dysmenorrhea may not begin until months or even up to three years after menarche, when ovulatory cycles become consistent. Risk factors in the occurrence and severity of dysmenorrhea include early menarche, longer menstrual cycles, smoking, alcohol intake, and weight greater than the 90th percentile. There does seem to be a slight familial tendency as women who experience dysmenorrhea tend to have daughters who also experience it.³

Diagnosis

For the most part, diagnosis of dysmenorrhea is based on patient history. Information about the age at menarche, age at the onset of dysmenorrhea, and medications that have been used should be obtained from the patient or her designee. The presence of additional symptoms such as nausea, vomiting, or diarrhea should also be noted as these symptoms are also prostaglandin-induced and help confirm the diagnosis. Family history is also pertinent due to the familial tendency toward dysmenorrhea. Once the history is obtained, a thorough physical exam should be completed including a pelvic exam if possible to rule out other causes of the pelvic pain. A pelvic exam should never be forced on a resistant or very young patient. In some situations, a rectal exam can be substituted for vaginal exam and still provide essential information. Further diagnostic procedures are unnecessary at this point, but may be indicated in the future if the patient does not respond to treatment.²⁰

Treatment

Since it is believed that the primary cause of dysmenorrhea is the stimulation of uterine contractions by prostaglandin F2a, it follows that the most appropriate treatment is the use of prostaglandin inhibitors such as NSAIDs. About 80 percent of all women will obtain relief from this category of drugs. These women may also note a decrease in the amount of menstrual bleeding, which is an additional benefit of this classification of drug. In general, these drugs also provide relief from other symptoms such as nausea, vomiting, and diarrhea commonly associated with dysmenorrhea.² A recent study of rofecoxib found that it was effective in treating primary dysmenorrhea in either a 25 mg or a 50 mg dose.¹⁵ Rofecoxib may not have many of the GI adverse effects associated with traditional or earlier NSAIDs, making it more accepted.²¹ 

Oral contraceptives have been found to reduce the pain associated with primary dysmenorrhea, which is thought to be a result of decreased prostaglandin synthesis associated with a thin, atrophic endometrial lining. Oral contraceptives not only relieve primary dysmenorrhea, but also provide benefits such as decreased menstrual bleeding and more regular cycles. Lifestyle changes such as weight loss, exercise, and decreased alcohol consumption may also result in improvement in symptoms.³

It is reasonable to allow three to six months of therapy before abandoning it. If patients do not respond to conservative management, a diagnostic laparoscopy may be considered to determine the cause of the symptoms.

Conclusion

Dysmenorrhea is more than just menstrual pain. It is a significant problem affecting the quality of life of many women and causing considerable absenteeism from both work and school. Research into the cause and treatment of dysmenorrhea should continue given its far-reaching economic and educational consequences.²⁰

Chapter 3: Hormonal Contraception

Unintended pregnancies remain a huge problem not only in the United States, but worldwide. Approximately half of all pregnancies are unintended.¹ In 2000, 1.31 million abortions occurred.² Forty-eight percent of women aged 15-44 have had unintended pregnancy, while 60 percent of women aged 35-39 have had an unintended pregnancy.²

Since the development of combination oral contraceptives some 40 years ago, approximately 200 million women worldwide have used birth control pills to prevent pregnancy.³ Despite this fact, the rate of unintended pregnancies continues to be a significant health problem. While information about contraception is increasingly available, confusion and mistrust concerning various contraceptive methods abounds.

In an effort to clear up many of the misconceptions and confusion, this chapter will focus on the various forms of hormonal contraception. Combination and progesterone-only oral contraceptive pills, Depo Provera, the Nuvaring, the Ortho Evra transdermal system, and IUDs will be discussed.

Oral contraceptives

Oral contraceptives can be described as combination or progesterone-only formulations. Combination oral contraceptives utilize the hormones estrogen and progesterone, while the progesterone-only formulations, as the name implies, are comprised of the hormone progesterone.^4-6

Combination oral contraceptives

The menstrual cycle was discussed in detail in Chapter 1. Understanding the role of hormones during the menstrual cycle helps in understanding the mechanism of action of hormonal contraception. A review of Chapter 1 may be helpful.

Recall that the hypothalamus releases gonadotropic releasing hormones (GnRH), which cause the pituitary to release follicle stimulating hormone (FSH) and luteinizing hormone (LH). FSH is responsible for stimulating the maturation of the ovarian follicles. The LH surge that occurs mid-cycle results in ovulation.⁵

Several factors make birth control pills an effective form of contraception. Initially, the release of gonadotropins is blocked at both the hypothalamic and pituitary levels. Progesterone is responsible for several actions that contribute to the effectiveness of oral contraceptives. First, it suppresses the LH surge, minimizing the likelihood of ovulation. It also makes the endometrial lining unreceptive to implantation and thickens the cervical mucus, which makes it difficult for sperm to penetrate and travel into the fallopian tube for fertilization.⁶

There are several different progestins used in the various oral contraceptive formulations: desogestrel, dropsirenone, ethynodiol diacetate, levonorgestrel, norethindrone, norethindrone acetate, norgestimate, and norgestrel.^5,7 It is the difference of the progesterone component that contributes to the uniqueness of various birth control pills. While all have similar contraceptive effects, there are some differences in androgenic properties. Androgen-related side effects include weight gain, nervousness, acne, and hirsutism. It is often the androgenic properties that lead to a woman’s dissatisfaction with and discontinuation of birth control pills.⁴

Estrogen is responsible for two mechanisms of action. First, it suppresses the release of FSH and thereby the selection of the dominant follicle. The second action is the stabilizing effect it provides to the endometrium. This effect helps to decrease the irregular shedding or breakthrough bleeding sometimes seen with contraceptive use. While these actions are important, another action that seems to be related to estrogen is its ability to potentiate the effect of the progesterone component, and thus allow lower dosages of progesterone to be used. Ethinyl estradiol, a potent form of oral estrogen, is the estrogen component used in nearly all oral contraceptive formulations. Mestranol, a weaker form of estrogen, is the other form of estrogen seen in oral contraceptives, but its use is currently limited to four formulations.^5,7 

Most oral contraceptive pills are taken for 28 days. The pills for the first 21 days contain various combinations of estrogen and progesterone, followed by seven days of inert (inactive) pills, thereby resulting in a 28-day cycle. The withdrawal of hormones that occurs when the inert pills are taken results in menstruation. Another new formulation consists of 21 active pills followed by two days of inert pills, then five days of an even lower dose of estrogen.⁵

Monophasic, multiphasic combinations

When oral contraceptives were first developed, all formulations were monophasic. That is, each active pill contained a fixed amount of estrogen and progesterone throughout the cycle. Later, it was discovered that total doses of progesterone could be decreased when estrogen and progesterone doses were varied within the 21-day cycle of active pills. These pills became known as multiphasic combinations. There are a few biphasic pills currently available, but they are not used often. Rather, the more common choice is the triphasic pill in which the dosages change three times during the active pill cycle.³ This can be either the progesterone or estrogen dosages.

Whether a monophasic, biphasic, or triphasic pill is used, the efficacy is the same as long as no pills are missed. However, because hormone metabolism varies significantly from person to person, it is not unusual to find that the same dose of one pill may cause a side effect in one woman and not in another.⁶ Clinicians are fortunate to have so many oral contraceptive options available. Table 6 and Table 7 list most of the oral contraceptives available.

Table 6

Table 7

Progesterone-only oral contraceptives

Also called the mini-pill, the progesterone-only pill contains progesterone and no estrogen. Unlike the combination pill, the mini-pill does not suppress ovulation. Its action is centered on its effect on endometrium and cervical mucus. The endometrium becomes hostile to implantation while the cervical mucus becomes thick and impermeable to sperm.⁶

This pill is most commonly used in breast-feeding patients, but may also be an option for women who have contraindications to estrogen use. It is felt that estrogen may inhibit milk production, and therefore, the mini-pill is often chosen over combination pills in the lactating woman. The progestin-only pill should be started at the six-week postpartum visit and is a suitable choice until supplemental feeding is started. Once formula supplements are introduced, it is wise to switch to a combination formulation that will provide more effective contraception.³

Contraindications

There is widespread misunderstanding among the public about the safety of oral contraceptives. In large part this is due to media misinformation. Several large-scale epidemiologic studies have failed to substantiate the risks most women cite as significant. In fact, these studies confirm the safety of oral contraceptives in healthy, non-smoking women.⁴ There are, however, absolute contraindications to oral contraceptives:⁶

• Thrombophlebitis, thromboembolic disorders, cerebral vascular disease, history of myocardial infarction, coronary occlusion, or conditions predisposing these conditions.
• Markedly impaired liver function
• Known or suspected breast cancer, endometrial cancer, or other estrogen-dependent neoplasia
• Undiagnosed abnormal vaginal bleeding
• Known or suspected pregnancy
• Smokers over the age of 35, smoking over 15 cigarettes a day

Relative contraindications such as hypertension, migraine headaches, diabetes, and epilepsy do exist. A patient with any of these conditions should review the safety of oral contraceptives with her clinician.⁶

One of the most common fears among women about oral contraceptives is the risk of developing breast cancer. It remains one of the top reasons women cite for not taking birth control pills.^5,12 Several studies have been conducted to investigate the risk of breast cancer in association with oral contraceptives. The Cancer and Steroid Hormone Study (CASH), conducted in the early 1980s by the national Centers for Disease Control and Prevention (CDC) and the National Institute of Child Health and Human Development, concluded that there was no overall association of breast cancer and new oral contraceptive use.⁸ Most recently, a large study by the Collaborative Group on Hormonal Factors in Breast Cancer found that there was no increase in the risk with dose or with increasing duration of risk. There was a small increase noted for current users and in the first 10 years after stopping oral contraceptives. There was no increase in risk 10 years or more after stopping oral contraceptives.^5,8,9  It was theorized that the additional cases of breast cancer seen in young current users or those who recently discontinued use were due to more frequent and regular exams by their physicians and therefore an increase in the rate of diagnosis. Types of progestin, family history of breast cancer, or ethnicity did not affect these rates.^5,8,9

The association of oral contraceptives with ischemic stroke has been studied frequently. Some studies have shown an increased risk of ischemic stroke in oral contraceptive users while other studies have shown that there is a protective effect. A meta analysis of the association of ischemic stroke and oral contraceptives was published in the Journal of the American Medical Association.¹⁰ This study compared the risk of ischemic stroke in oral contraceptive users with the risk of stoke and death as a result of unintended pregnancy. If condoms replaced oral contraceptives, there would be an additional 687,000 unintended pregnancies with 26 strokes and 33 deaths based on the complications of pregnancy, delivery, or abortion. The study concluded that while oral contraceptive use is associated with an increased risk of ischemic stroke, the absolute numbers are small and the occurrence of stroke is unlikely given the smaller doses of estrogen in today’s oral contraceptives.¹¹ 

Extended-cycle oral contraceptives

Late in 2003, the FDA approved Seasonale, an oral contraceptive that is taken continuously for 12 weeks, followed by one-week of inactive pills.¹¹ Historically, the concept of a monthly withdrawal bleed was thought to be more acceptable to women and perhaps reassuring to the health care provider. In the next section, noncontraceptive benefits of oral contraceptives will be reviewed. The noncontraceptive benefits of oral contraceptives serves as the rationale for an extended-use method. Extended-use oral contraceptives are taken the same way as conventional oral contraceptives. Breakthrough bleeding is common during the first extended cycle, and the discontinuation rate is higher in these pill takers than conventional oral contraceptive users. Disadvantages include a potential delay in diagnosis of pregnancy, later gestation if abortion is desired, a potential for pregnancy contraindicated drug use or alcohol use during pregnancy, and the same risks as outlined for monthly cyclic oral contraceptives.²³

Benefits to oral contraceptives

Women rarely consider the benefits of oral contraceptives when choosing a method of contraception; the adverse effects and risks are more frequently discussed. There are many well-documented benefits to oral contraceptives, and no discussion of their use would be complete without at least a brief discussion of their benefits.^5,6,12

Ovarian cancer is a frightening disease. Usually asymptomatic until the latter stages, ovarian cancer has already metastasized at the time of detection in about 75 to 80 percent of cases. The five-year survival rate is about 40 to 45 percent. In several studies, oral contraceptive use has been found to decrease the incidence of ovarian cancer. Protection lasts for 15 to 20 years after discontinuation of oral contraceptives. The mechanism of action is thought to be due to the suppression of repetitive ovulatory cycles or reduction of pituitary gonadotropin levels.^5,6,12 

While ovarian cancer is more deadly, there is a higher incidence of endometrial cancer. Endometrial cancer is reduced after only 12 months of oral contraceptive use. Extended use seems to provide c