Catherine M. Gordon
Lawrence S. Neinstein
Amenorrhea is defined by a variety of diagnostic criteria. However, strict adherence to these criteria can potentially lead to improper management. Chronological age and developmental stage, in association with clinical data, must be integrated into the criteria for establishing a diagnosis of amenorrhea. Such guidelines are listed in this chapter. The need for evaluation can be determined by the number of criteria that are present.
A brief review of normal development is essential in determining abnormalities of the menstrual cycle.
and consider clinical evidence of other autoimmune phenomenons, such as hypothyroidism, hypoparathyroidism, or type 1 diabetes.
This condition is extremely rare. The individual usually has a male karyotype, elevated gonadotropin levels, and testosterone values that are either equal to or less than the level in a healthy female. These individuals produce enough MIF to inhibit development of female internal genital structures, but not enough testosterone to develop male internal and external genitalia. The causes include the following:
The pulsatile nature of LH, and thereby normal menstrual function, appears to be dependent on energy availability (caloric intake minus energy expenditure). Low energy availability appears to result in a hypometabolic state that can include the metabolic alterations, hypoglycemia, hypoinsulinemia, euthyroid sick syndrome (low total triiodothyronine [T3]), hypercortisolemia, and suppression of the total secretion and amplitude of the diurnal rhythm of leptin (American Academy of Pediatrics, Committee on Sports Medicine and Fitness, 2000; Laughlin and Yen, 1997). Leptin, a hormone secreted by fat tissue, has been shown to be a permissive factor in menstruation, likely due to its correlation with adequate fat mass (Welt et al., 2004). Although both amenorrheic athletes and regularly menstruating athletes have reduced LH pulsatile secretions and reduced 24-hour mean leptin levels, amenorrheic runners have more extreme suppression and disorganization of LH pulsatility. The level of energy availability needed to maintain normal reproductive function is not known. Exercise-induced
menstrual dysfunction may also relate to elevated dopamine or endorphin levels altering GnRH/LH secretion. Constantini and Warren (1995) report on amenorrhea in swimmers. Results from their study suggest that female competitive swimmers are vulnerable to delayed puberty and menstrual irregularities, but the associated hormonal profile is different from that described in dancers and runners. Their study suggests a different mechanism for reproductive dysfunction in swimmers that is associated with mild hyperandrogenism, rather than with hypoestrogenism. Predisposing factors to exercise-induced amenorrhea include the following:
Low levels of estradiol (E2) may be present, which has been implicated as the cause of bone loss, placing these young women at increased risk of stress fractures. The condition may be reversible with weight gain or with lessening of the intensity of exercise; however, there is also evidence that this loss of bone density might be partially irreversible despite resumption of menses, estrogen replacement, or calcium supplementation. There are many questions about exercise-induced amenorrhea that remain unanswered, especially related to whether estrogen replacement therapy is beneficial in minimizing skeletal loss in this population.
Premature ovarian failure: Menopause occurring at younger than 35 years. This is often associated with autoantibodies directed against ovarian tissue and may be found in association with thyroid and adrenal autoantibodies. This can also occur in some individuals who received chemotherapy and/or radiation therapy for cancer as children or adolescents (Byrne et al., 1987, 1992; Shalet, 1980; Stillman et al., 1981; Waxman, 1983).
The evaluation of amenorrhea can be done with a thorough history, physical examination, and performance of several laboratory tests in a logical sequence. Too often, adolescents are subjected to an expensive “shotgun” approach to evaluation. It is essential to rule out the diagnosis of pregnancy before conducting an extensive evaluation.
History should include the following:
The physical examination should include the following:
most adolescents are not menarcheal until SMR 4, and 95% are menarcheal by 1 year after SMR 5.
The laboratory evaluation for adolescents can be done on the following basis:
Figures 52.1 and 52.2 review the evaluation of primary and secondary amenorrhea.
FIGURE 52.1 The evaluation of primary amenorrhea.
If the results of the aforementioned evaluation are negative, the work-up should proceed as follows (Fig. 52.2):
Administer progesterone withdrawal test or “challenge”: A positive response correlates with circulating E2 levels adequate to prime the endometrium. A positive response (ranges from minimal brown staining to normal menstrual flow) indicates a serum E2 level >40 pg/mL.
If the teen has a normal prolactin level, she would not require an MRI unless otherwise indicated on the history and physical examination. However, a prolactin test would be indicated every 6 to 12 months if there are no spontaneous menses. An MRI should always be considered in a female patient with a history of headaches or visual changes.
In general, breast development should be at least at stage SMR 4 to be considered indicative of full gonadal function. A breast stage of SMR 2 or SMR 3 may indicate adrenal function alone without gonadal function.
Hypothalamic Hypogonadotropic Hypogonadism (Hypothalamic Failure)
Therapy should begin with estrogen therapy (0.3 mg/day or less if the adolescent is short to avoid premature epiphyseal closure). A transdermal patch can be used to start at 0.025 mg/day of estradiol, or half of the 0.3 mg-Premarin pill can be utilized. Patients with normal height can receive up to 0.625 mg/day of conjugated estrogen (Premarin) or 0.1 mg of estradiol via transdermal patch. High doses of estrogen and premature introduction of progesterone should be avoided early to prevent abnormal breast development manifested by increased subareolar breast development and abnormal contours.
FIGURE 52.2 The evaluation of secondary amenorrhea. TSH, thyroid-stimulating hormone; PCOS, polycystic ovary syndrome; CT, computed tomography; MRI, magnetic resonance imaging; FSH, follicle-stimulating hormone; LH, luteinizing hormone; CNS, central nervous system.
A typical maintenance schedule would be 0.625 to 1.25 mg/day of conjugated estrogens on days 1 through 25 of each month or twice-weekly estrogen patch application of 0.1 mg of estradiol, with 10 mg of medroxyprogesterone acetate (Provera) on days 12 through 25. The progestin is added to induce withdrawal bleeding and thereby avoid endometrial hyperplasia. This schedule can be repeated each month. The dose of estrogen may range from 0.625 to 2.5 mg/day, depending on the individual and the estrogen response, but usually does not exceed 1.25 mg/day of conjugated estrogens. GnRH will probably be used for these conditions when a more easily tolerated delivery system is available. If pregnancy is desired, pulsatile GnRH is an option.
Hormonal therapy, as outlined.
Genetic Abnormalities Leading to Gonadal Defects
Hormonal therapy, as already outlined. If a Y chromosome is present in an XX-karyotyped individual, gonadal removal is necessary because of the risk of gonadoblastoma development. If a 46,XX karyotype is present, then the gonadal tissue should be visualized to assess whether more than a streaked gonad is present. It is important to start hormonal replacement therapy in early adolescence. With complete
gonadal dysgenesis, these individuals are universally sterile. However, with an intact uterus, the individual could be able to bear children after donor oocyte implantation and hormonal support.
For 17α-hydroxylase deficiency, both glucocorticoid and estrogen-progesterone replacement are needed and removal of gonads is needed if Y chromosome is present. For 17,20-lyase deficiency, prescribe estrogen–progesterone replacement; remove gonads if Y chromosome is present.
Congenital Absence of the Uterus
Because these adolescents have normal-functioning ovaries, they do not require hormonal replacement therapy. They may require a vaginoplasty for normal sexual function and an MRI or intravenous pyelogram to rule out renal anomalies. These adolescents must be informed that they cannot become pregnant; therefore, they may require additional support and counseling regarding their identity and body image.
Primary and Secondary Amenorrhea with Normal Secondary Sexual Characteristics
Amenorrhea Associated with Weight Loss
In young women with amenorrhea associated with weight loss, bone mineral density (BMD) loss can occur soon after amenorrhea develops. Treatment to prevent BMD loss or to promote bone accretion should probably start after 6 months of amenorrhea (Hergenroeder, 1995). The efficacy of estrogen replacement therapy in this setting is an area of debate. Estrogen likely has beneficial effects on bone and other tissues, but other supplemental therapies may also be warranted. Experimental therapies, such as low-dose androgen supplementation (dehydroepiandrosterone [DHEA] or testosterone), insulin-like growth factor 1 (IGF-1) or growth hormone, and bisphosphonates are gaining further support in the literature (Gordon, 1999; Gordon et al., 2002; Grinspoon et al., 2002; Miller et al., 2005; Golden et al., 2005). Most adolescents who recover from anorexia nervosa at a young age (younger than 15 years) can have normal total-body BMD, but regional (lumbar spine and femoral neck) BMD may remain low (Hergenroeder, 1995). The longer the duration of anorexia nervosa and/or weight loss, the less likely the BMD will return to normal values.
The Female Athlete Triad
Female children and adolescents who participate regularly in athletics may develop the female athlete triad, which includes disordered eating, menstrual dysfunction (typically amenorrhea), and decreased BMD (Goodman and Warren, 2005).
persists for 6 months with bone loss, the bone mass may never be regained, whereas other studies indicate a 20% increase in bone mass when weight is gained. Baer (1993)compared reproductive function in ten amenorrheic and eumenorrheic adolescent female runners and seven untrained controls. Amenorrheic subjects were found to run more miles per day and consume fewer calories per day compared with eumenorrheic subjects. Mean levels of fasting plasma E2, LH, FSH, free T4, and T3 were significantly lower in amenorrheic patients compared with eumenorrheic patients and the control subjects. In addition, those who were amenorrheic indicated that they were very concerned about their weight and fearful of gaining fat mass. Other studies have indicated that the change in bone density may also relate to the type of athletics performed—with gymnastic exercises, for example, yielding a stronger bone mass. One recent Scandinavian study demonstrated that most women who exercise regularly at moderate levels are not at significant risk for athletic amenorrhea with its accompanied decrease in BMD. Summary considerations for athletes with amenorrhea include the following (Hergenroeder, 1995):
Polycystic Ovary Syndrome
PCOS is a disorder of the hypothalamic-pituitary-ovarian system, giving rise to temporary or persistent anovulation and androgen excess. The syndrome was originally described in 1935 by Stein and Leventhal as amenorrhea, hirsutism, and obesity associated with enlarged cystic ovaries. For many years, there was an emphasis on the morphological changes in the ovary. However, enlarged polycystic ovaries may occur in healthy women and in women with other conditions such as Cushing syndrome and congenital adrenal hyperplasia (CAH). In addition, women with other classic features of PCOS may have ovaries of normal size. A 1990 U.S. NIH consensus conference identified key features for the diagnosis of PCOS—hyperandrogenism, menstrual dysfunction, clinical evidence of hyperandrogenism, and the exclusion of CAH. Probable criteria for PCOS included insulin resistance and perimenarchal onset.
The 2003 Rotterdam consensus workshop defined PCOS more broadly, recognizing ovarian dysfunction as the primary component, without mandatory anovulation. The revised definition included two of the three following criteria with the exclusion of other etiologies of hyperandrogenism:
The consensus definitions are broad, allowing for a clinical and biochemical diagnosis of a wide spectrum of phenotypes. Diagnosis is particularly important because PCOS is now believed to increase metabolic and cardiovascular risks, which is linked to insulin resistance and compounded by obesity. Insulin resistance and its associated risks are also present in nonobese women with PCOS. PCOS is one of the most common endocrine disorders, affecting approximately 5% to 10% of premenopausal women and is the most common cause of hyperandrogenism in women and girls.
PCOS is characterized by menstrual irregularities ranging from amenorrhea or oligomenorrhea, to dysfunctional uterine bleeding. An androgen-excess state is present, leading to hirsutism and acne with rare mild virilization. The changes in gonadotropins and steroid hormones that cause these manifestations are as follows:
The exact initiating cause of PCOS is not known but may be related to the following:
Factors leading to the development of PCOS include the following:
Gulekli et al. (1993) compared adolescent girls with PCOS and adult women with PCOS and found that clinical manifestations and hormonal changes were similar. In addition, the rates of insulin resistance and glucose intolerance found in adolescent girls with PCOS are similar to the rates in adult women, of up to 30% (Palmert et al., 2002).
Valproate can also induce menstrual disturbances, polycystic ovaries, and hyperandrogenism (Isojarvi et al., 1993). In a study of 238 women with epilepsy, Isojarvi et al. found 43% of the women using valproate had polycystic ovaries. In those women using valproate before reaching age 20 years, 80% had polycystic ovaries or hyperandrogenism.
PCOS can present with many symptoms. Table 52.1 indicates the prevalence of various signs and symptoms associated with PCOS.
waist-hip ratios. The obesity with PCOS also worsens insulin resistance and increases cardiovascular risks. In obese women, weight loss may improve and/or cure the signs and symptoms of PCOS.
Criteria for the diagnosis of PCOS include the following:
The following are not needed for diagnosis but are supportive evidence of the diagnosis:
Infertility is usually not a concern in the adolescent patient. However, when fertility is desired, clomiphene citrate and/or metformin therapy may be used to stimulate ovulation. The use of exogenous gonadotropins is also found in research and clinical practice.
Oral contraceptives work in the following manner:
In addition to oral contraceptives, antiandrogens such as spironolactone can be used (see Chapter 50). The combination of low-dose oral contraceptives and spironolactone is very effective. Antiandrogen therapies have been used as primary and secondary therapeutics in the treatment of PCOS. Results have been conflicting as to the contribution to improving insulin resistance (Dunaif et al., 1990; Moghetti et al., 2000). Antiandrogens include spironolactone and cyproterone acetate which interfere with steroidogenesis. These medications are most often used in combination with estrogen or combined estrogen/progestin therapy (Yasmin). Although, spironolactone has some effect in ameliorating the clinical effects of hyperandrogenism, when used without additional hormonal therapy irregular menstrual bleeding is common.
The patient with amenorrhea or oligomenorrhea can receive medroxyprogesterone acetate (Provera) (10 mg daily for 10 days every 6 to 12 weeks) for withdrawal bleeding. However, the monthly use of medroxyprogesterone acetate has no significant effect on androgen production by the ovaries, so it is not helpful if hirsutism is present.
Obesity may be a major focus of preventive health care for women with PCOS to lower associated cardiovascular risks and insulin resistance. Lifestyle modification with dietary and activity interventions should be the initial intervention in obese women with PCOS. However, weight loss is difficult to achieve. Older adolescents and young adults with morbid obesity (BMI >40 kg/m2 or BMI >35 kg/m2 and secondary complications, such as hypertension, sleep apnea, cardiovascular disease, and PCOS) may be candidates for medication use and/or surgical therapy.
Because of the potential for abnormal glucose tolerance (insulin resistance) and hyperlipidemia, it can be important to evaluate these factors in adolescents with PCOS and to consider therapeutic interventions. The use of insulin-sensitizing medications in the treatment of PCOS has recently become an area of great interest. Many clinicians and scientists favor the treatment of insulin resistance in women with PCOS because these women are at increased risk for the development of type 2 diabetes and cardiovascular disease. In addition, the reduction of hyperandrogenism by hormonal therapy does not correct the hyperinsulinism (Nestler, 1997). The use of insulin-sensitizing agents such as metformin may reduce the risk of hyperinsulinism, type 2 diabetes, and the metabolic syndrome (Knowler et al., 2002; Morin-Papunen et al., 2003). In addition, the reduction in hyperinsulinism has been shown to induce ovulation and regulation of menstrual cycling (Velazquez et al., 1994; Fleming et al., 2002; Baillargeon et al., 2003). Studies have shown that the use of metformin in young adolescents with PCOS may regulate menstrual cycling and reduce the clinical hyperandrogenic effects. In addition, metformin may be able to prevent the development of the PCOS phenotype in young girls with premature adrenarche (Morin-Papunen et al., 2000; Glueck et al., 2001; Ibanez et al., 2004). These remain areas of active research.
Women with PCOS should have their cholesterol, triglycerides, and both LDL-C and HDL-C measured, although there is no consensus at what age this should be done and how often the tests should be rechecked if the
results are normal. In addition, these women should be checked and followed for impaired glucose tolerance and diabetes. The screening evaluation for abnormal glucose metabolism is an area of continued debate. The current American Diabetes Association recommendations for pediatric diabetes screening include the evaluation of a fasting blood sugar every 2 years, beginning at age 10 years or puberty, in all children who are overweight, as defined by a BMI of greater that the 85th percentile for age and sex, weight for height >85th percentile, or weight >120% of ideal for height plus any two of the designated risk factors:
PCOS is listed as a condition associated with insulin resistance, and therefore, the diagnosis of PCOS in an adolescent who is obese and has a family history of diabetes or a high-risk ethnicity meets the criteria for a fasting blood glucose screening. However, there is growing evidence that lean adolescents with PCOS may also be at risk for insulin resistance and that both lean and obese girls with PCOS may benefit from oral glucose tolerance testing (oral glucose challenge of 1.75 g/kg up to a maximum of 75 g) (Palmert et al., 2002). The absence of obesity and acanthosis nigricans does not rule out insulin resistance in the presence of clinical hyperandrogenism. Diagnosis and continued monitoring of these individuals may reduce the risk of metabolic and cardiovascular disease. Reduction in insulin resistance is important, and diet and exercise are critical first-line steps. Insulin-sensitizing medications may prove beneficial, but a consensus regarding guidelines for their usage has not been reached to date for adolescents with PCOS.
For Teenagers and Parents
http://www.youngwomenshealth.org/. Children's Hospital Boston Adolescent and Young Adult Program Web site.
http://www.goaskalice.columbia.edu/0814.html. Go Ask Alice site for missed periods.
http://www.nlm.nih.gov/medlineplus/ency/article/001218. htm. National Library of Medicine on amenorrhea.
http://www.turner-syndrome-us.org. The Turner's Syndrome Society of the United States. This Web site provides information and allows young women to exchange information.
http://www.medhelp.org/ais/. Androgen Insensitivity Syndrome Support Group. This site contains medical information about androgen insensitivity, support group contacts, newsletters, and personal accounts of people with androgen insensitivity syndrome.
Polycystic Ovary Syndrome Web Sites
http://www.pcosupport.org/. The PCOS Association's Web site includes facts and figures on PCOS, as well as on-line support.
http://www.pcosupport.org/living/teen/. The PCO Teenlist home page is dedicated to teenagers with PCOS. Includes a chat room and bulletin board so teens can share their thoughts on the disease.
http://www.obgyn.net/pcos/pcos.asp. PCOS Pavilion.
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