Adolescent Health Care: A Practical Guide

Chapter 52

Menstrual Disorders: Amenorrhea and the Polycystic Ovary Syndrome

Amy Fleischman

Catherine M. Gordon

Lawrence S. Neinstein

Amenorrhea

Definition

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.

• For the American adolescent, the average age at menarche is 12.7 years, with a two standard deviation range of 11 to 15 months. Although there have been some reports of a trend toward younger ages for pubertal initiation, the average age at menarche seems to have remained stable.
• Ninety-five percent to 97% of females reach menarche by age 16 years and 98% by 18 years.
• There is an average of 2 years between the start of thelarche, the first sign of puberty, and the onset of menarche.
• The onset of menarche is fairly constant in adolescent development, with approximately two thirds of females reaching menarche at a Tanner sexual maturity rating (SMR) of 4. Menarche occurs at SMR 2 in 5% of girls, SMR 3 in 25%, and not until SMR 5 in 10%.
• Ninety-five percent of teens have attained menarche 1 year after attaining SMR 5.

1. Primary amenorrhea
2. No episodes of spontaneous uterine bleeding by the age of 14 years with secondary sexual characteristics absent.
3. No episodes of spontaneous uterine bleeding by age 16 years regardless of normal secondary sexual characteristics (chronological criteria).
4. No episodes of spontaneous uterine bleeding, despite having attained SMR 5 for at least 1 year or despite the onset of breast development 4 years previously (developmental criteria).
5. No episodes of spontaneous uterine bleeding by age 14 years in any individual with clinical stigmata of or genotype consistent with Turner syndrome.
6. Secondary amenorrhea: After previous uterine bleeding, no subsequent menses for 6 months or a length of time equal to three previous cycles.

Etiology

1. Primary amenorrhea without secondary sexual characteristics (absent breast development), but with normal genitalia (uterus and vagina)
2. Genetic or enzymatic defects causing gonadal (ovarian) failure (hypergonadotropic hypogonadism): Approximately 30% of primary amenorrhea cases are secondary to a genetic cause. The most common disorders are as follows:

• Turner syndrome, Turner mosaicism or related genotypes (45,X; 45,XX/X; or 45,XY/X: Stigmata are variable in mosaicism, but classically include short stature (height usually<60 in.); streaked gonads; sexual infantilism; and somatic anomalies (webbed neck, short fourth metacarpal, cubitus valgus, coarctation of the aorta).
• Structurally abnormal X chromosome: Phenotype varies. Long-arm deletion commonly causes normal stature, no somatic abnormalities, streaked gonads, and sexual infantilism. Short-arm deletion defects lead to a phenotype similar to that of Turner syndrome.
• Mosaicism: X/XX. Eighty percent of such individuals are short, 66% have some somatic anomaly, and 20% have spontaneous menses. The characteristics for X/XXX and X/XX/XXX individuals are similar to those for X/XX individuals.
• Pure gonadal dysgenesis (46,XX or 46,XX/XY with streaked gonads): Stigmata include normal stature, streaked gonads, sexual infantilism, and usually no somatic abnormalities. Etiologies can include autoimmunity, and enzymatic or genetic abnormalities. The etiology may be important in directing further evaluation and in counseling families. For example, a fragile X premutation in a female carrier can cause ovarian failure while future generations in the family would be at risk for severe mental retardation in males. Evidence of autoimmunity, such as ovarian and/or adrenal antibodies, suggests the need to evaluate adrenal status

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and consider clinical evidence of other autoimmune phenomenons, such as hypothyroidism, hypoparathyroidism, or type 1 diabetes.

• 17α-hydroxylase deficiency with 46,XX karyotype: These individuals have normal stature, sexual infantilism, hypertension, and hypokalemia. Their laboratory test results show an elevated progesterone (>3 ng/mL), low 17α-hydroxyprogesterone (<0.2 ng/mL), and elevated serum deoxycorticosterone level.

1. Isolated pituitary gonadotropin insufficiency: Very rare. Kallmann syndrome should be considered and can be associated with anosmia.
2. Hypothalamic failure secondary to inadequate gonadotropin-releasing hormone (GnRH) release.
3. Primary amenorrhea with normal breast development, but absent uterus
4. Complete androgen insensitivity (formerly testicular feminization): In these XY-karyotype individuals, the Wolffian ducts fail to develop and external female genitalia are present in the absence of a response to testosterone stimulation. The underlying defect is a mutation in the androgen receptor, rendering it insensitive to testosterone's actions. Because müllerian inhibitory factor (MIF) continues to be secreted by the Sertoli cells of the male gonads, the müllerian ducts regress, and there is lack of formation of internal female genitalia. Internally, the teen has normal male gonads and fibrous müllerian remnants. At puberty, the low levels of endogenous gonadal and adrenal estrogens, unopposed by androgens, result in breast development. Because of the end-organ insensitivity to androgens, the teen develops sparse or absent pubic and axillary hair. In summary, manifestations include the following:

• 46,XY karyotype
• Female phenotype in the case of complete androgen insensitivity (genital ambiguity often presents in incomplete forms)
• Testes present in abdomen, pelvis, or inguinal canal
• Lack of axillary and pubic hair
• Normal breast development
• Blind vaginal pouch with absence of ovaries, uterus, and fallopian tubes
• Normal or elevated male testosterone concentrations

1. Congenital absence of uterus

• 46,XX karyotype
• Ovaries are present: These adolescents may experience cyclic breast and mood changes
• Normal secondary sexual characteristics
• Uterus absent or rudimentary cords
• Absent or blind vaginal pouch
• Normal female testosterone concentration
• May have associated renal, skeletal, or other congenital anomalies

3. Primary amenorrhea with no breast development and no uterus:

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:

1. 17,20-Lyase deficiency
2. Agonadism, including no internal sex organs
3. 17α-Hydroxylase deficiency with 46,XY karyotype: Manifestations include sexual infantilism, absent uterus, and hypertension.
4. Primary and secondary amenorrhea with normal secondary sexual characteristics (breast development) and normal genitalia (uterus and vagina)
5. Hypothalamic causes

• Idiopathic: Usually associated with a normal response of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to GnRH. The disorder is probably secondary to a subtle defect in GnRH secretion. Unstimulated levels of FSH and LH are typically within the low-normal reference range.
• Medications and drugs: Particularly phenothiazines, oral, injectable or transdermal contraceptives, glucocorticoids, and heroin.
• Other endocrinopathies: Hyperthyroidism or hypothyroidism, and cortisol excess
• Stress: Common in adolescents and may relate to family, school, or peer problems, or to a fear of pregnancy
• Exercise: Athletes, particularly runners, gymnasts, competitive divers, figure skaters, and ballet dancers, have higher rates of amenorrhea and higher rates of disordered eating (female athlete triad includes a combination of disordered eating, amenorrhea, and decreased bone density). Sports that may place athletes at higher risk for this condition include those that emphasize leanness, such as dance or gymnastics, or those that use weight classification, such as martial arts. The prevalence of secondary amenorrhea in adult athletes ranges from 3.4% to 66% depending on the sport studied (American Academy of Pediatrics, Committee on Sports Medicine and Fitness, 2000). As many as 18% of female recreational runners, 50% of competitive runners training 80 m/week, and 47% to 79% of ballet dancers may be amenorrheic (Goodman and Warren, 2005; Eliakim and Beyth, 2003; Calabrese et al., 1983; Cumming and Rebar, 1983). The prevalence of secondary amenorrhea in the teen athlete is unknown.

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

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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:

• –Training intensity
• –Weight loss
• –Changes in percentage of body fat
• –Nulliparity
• –Menstrual dysfunction before exercise
• –Years of intense training before the onset of menarche

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.

• Weight loss: This group includes adolescents with simple weight loss and those with anorexia nervosa (see Chapter 33). In both patients with anorexia nervosa and patients with simple weight loss, the mechanism of amenorrhea appears to be hypothalamic derangement. This derangement appears to be more severe in adolescents with anorexia nervosa. The E₂levels in patients with weight loss and anorexia nervosa can vary from low to normal. Consequently, such individuals may or may not respond to progesterone withdrawal with uterine bleeding. The teens with amenorrhea and severe weight loss also are at risk for decreased bone density.
• Chronic illnesses: Certain chronic illnesses can affect the hypothalamic-pituitary axis. Examples include cystic fibrosis (Moshang and Holsclaw, 1980; Neinstein et al., 1983) and chronic renal disease (Mooradian and Morley, 1984).
• Hypothalamic failure
• –Idiopathic
• –Lesions: rare, include craniopharyngioma, tuberculous granuloma, or meningoencephalitis
• Polycystic ovary syndrome (PCOS): Many researchers believe PCOS to be primarily a hypothalamic disorder. More than half of affected individuals have an LH : FSH ratio >3, with an LH level >10 mIU and often >25 mIU (see “PCOS” section)

1. Pituitary causes

• Nonneoplastic lesions resulting in hypopituitarism: Sheehan syndrome (pregnancy related), Simmonds disease (nonpregnancy related), aneurysm, or empty sella syndrome
• Tumors: Adenoma or carcinoma
• Idiopathic
• Infiltrative: Hemochromatosis

1. Ovarian causes

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).

1. Uterine causes: Uterine synechiae (Asherman syndrome)
2. Pregnancy

Diagnosis

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

History should include the following:

1. Systemic diseases: Diseases associated with secondary amenorrhea should include anorexia nervosa, inflammatory bowel disease, diabetes mellitus, and pituitary adenoma. A history of thyroid dysfunction is particularly important, because even mild thyroid dysfunction can lead to menstrual abnormalities.
2. Family history, including ages of parental growth and development, mother's and sister's ages at onset of menarche, as well as a family history of any thyroid disease, diabetes mellitus, eating disorders, or menstrual problems.
3. Past medical history including childhood development.
4. Pubertal growth and development, including breast and pubic hair development, and the presence of a growth spurt.
5. Emotional status.
6. Medications: Including illicit drugs (heroin and methadone are strongly correlated with menstrual dysfunction).
7. Nutritional status and recent weight changes.
8. Exercise history, particularly for sports that might predispose to amenorrhea.
9. Sexual history, contraception, and symptoms of pregnancy.
10. Menstrual history.
11. History of androgen excess suggesting PCOS, or another ovarian or adrenal abnormality.

Physical Examination

The physical examination should include the following:

1. Check for signs of systemic disease or malnutrition.
2. Evaluate for SMR: This is important for evaluating progress in secondary sexual characteristics, because

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most adolescents are not menarcheal until SMR 4, and 95% are menarcheal by 1 year after SMR 5.

3. Check height and weight.
4. Check for signs of androgen excess such as acne or hirsutism.
5. Check for signs of thyroid dysfunction.
6. Check for signs of insulin resistance such as acanthosis nigricans, hyperpigmented velvety skin changes on neck, axillae, or other intertriginous areas.
7. Check for signs of gonadal dysgenesis: Webbed neck, low-set ears, broad shield-like chest, short fourth metacarpal, and increased carrying angle of the arms.
8. Test for anosmia in females with primary amenorrhea to evaluate for Kallmann syndrome.
9. Breast examination: Check for galactorrhea.
10. Pelvic examination: Search for a stenotic cervix, vaginal agenesis, imperforate hymen, transverse vaginal septum, absent uterus, or pregnancy. An external genital examination is a critical component of the work-up. A full pelvic examination may not be necessary if the teen is not sexually active, and the history or physical examination has revealed the cause of amenorrhea.

Laboratory Evaluation

The laboratory evaluation for adolescents can be done on the following basis:

• Primary and secondary amenorrhea with normal secondary sexual characteristics and normal genitalia
• Primary amenorrhea and absent secondary sexual characteristics or absent uterus or vagina

Figures 52.1 and 52.2 review the evaluation of primary and secondary amenorrhea.

FIGURE 52.1 The evaluation of primary amenorrhea.

1. Evaluation for primary and secondary amenorrhea with normal secondary sexual characteristics:
2. If evidence of galactorrhea or androgen excess is present, the adolescent should be evaluated, as described in Chapters 57 and 58, respectively.
3. Pregnancy should always be considered and ruled out.
4. Diabetes mellitus and hypothyroidism should be considered and if clinically indicated, should be ruled out with measurements of blood sugar or thyroid function tests.
5. Uterine synechiae, or Asherman syndrome, should be considered if there is a history of dilation and curettage or endometritis. This condition may cause partial or total obliteration of the uterine cavity. If this problem is suggested by the history, a gynecological referral for evaluation by hysteroscopy or hysterosalpingography is indicated.

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.

• A positive response to progesteroneindicates the presence of adequate estrogen levels, as seen with either hypothalamic-pituitary dysfunction or PCOS.
• –Prolactin level should be measured, because this is the most sensitive test for pituitary microadenomas. Rarely, a patient who responds to progesterone withdrawal can have a microadenoma.
• –In addition, thyroid-stimulating hormone and T₄should be measured to rule out the possibility of either primary or central hypothyroidism.
• –LH or LH : FSH ratios have been used in the past to evaluate for PCOS. However, these values lack sensitivity and specificity.
• If there is no response to progesterone, then either hypothalamic-pituitary dysfunction or ovarian failure is likely. A high FSH level indicates ovarian failure, whereas a normal or low FSH level suggests a hypothalamic-pituitary disturbance. If ovarian failure is suspected, a karyotype, antiovarian antibodies, and screening for autoimmune endocrinopathies should be considered. If hypothalamic-pituitary failure is suspected, a magnetic resonance imaging (MRI), visual fields, and pituitary stimulation tests should be considered.

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• Individuals with weight loss, anorexia nervosa, heavy substance abuse, or heavy exercise may or may not respond to progesterone withdrawal. If they do not experience bleeding within 10 to 14 days of discontinuing the progesterone, it is indicative of low E₂levels.

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.

2. Evaluation for primary amenorrhea with either absent uterus or absent secondary sexual characteristics (Fig. 52.1):
3. A physical examination will divide the teens into three groups:

• Absent uterus, normal breasts
• Absent breasts, normal uterus
• Absent breasts, absent uterus

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.

1. If the examination reveals normal breast development, but an absent uterus and blind vaginal pouch, a karyotype and a test for serum testosterone concentrations are indicated.

• XX karyotype plus female testosterone concentration: Congenital absence of uterus
• XY karyotype plus male testosterone concentration: Androgen insensitivity

1. If the examination reveals absent secondary sexual characteristics, but a normal uterus, an FSH test is ordered.

• A low or normal FSH level suggests a hypothalamic or pituitary abnormality, and a careful neuroendocrine evaluation is in order.
• A high FSH level and a blood pressure within the reference range suggest a genetic disorder or gonadal dysgenesis. A karyotype should be ordered.
• A high FSH level and hypertension suggest 17α-hydroxylase deficiency. This is confirmed by an elevated progesterone level (>3 ng/mL), low 17α-hydroxyprogesterone level (<0.2 ng/mL), and an elevated serum deoxycorticosterone level.

1. The absence of both breast development and uterus or vagina is very rare. These findings suggest gonadal failure and the presence of MIF secretion from a testis. This could arise from anorchia occurring after MIF activity was present or an enzyme block, such as a 17,20-lyase defect. The evaluation should include LH, FSH, progesterone, and 17-hydroxyprogesterone measurements, and a karyotype.

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Treatment

Primary Amenorrhea

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.

Pituitary Defect

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

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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.

Enzyme Defects

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.

Androgen Insensitivity

1. Gonadal removal: All intraabdominal gonads associated with a Y chromosome have a relatively high potential for malignancy and should be removed. The appropriate timing for removal should be individualized for each patient.
2. After the testes are removed, maintenance estrogen therapy is needed.
3. The adolescent should be informed that she may require vaginoplasty to have normal sexual function.
4. The adolescent should be informed that she cannot become pregnant.
5. Counseling: The adolescent should be informed that she has an abnormal sex chromosome. She may require extra reassurance and counseling regarding her identity and concerns about infertility and sexual function.

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

1. PCOS
2. Medroxyprogesterone acetate (10 mg) should be given for 10 days every 1 to 2 months to induce withdrawal bleeding, or estrogen and progestins can be given as oral contraceptive pills with or without spironolactone.
3. Insulin-sensitizing agents should be considered, particularly in adolescent girls with clinical (acanthosis nigricans) or biochemical evidence of hyperinsulinism.
4. When pregnancy is desired, referral for use of clomiphene citrate and/or insulin-sensitizing agents, such as metformin can be recommended.
5. Hypothalamic-pituitary dysfunction
6. Alleviate the precipitating cause, if known.
7. Hormonal therapy with progestins to induce uterine bleeding every 1 to 2 months is recommended.
8. Hypothalamic-pituitary failure
9. The cause must be evaluated and corrected if possible.
10. Replacement therapy with cyclic conjugated estrogens and progestins, as outlined earlier for hypothalamic failure, is recommended.
11. If the adolescent or young adult desires pregnancy, refer her to an infertility clinic.
12. Ovarian failure
13. These adolescents also require cyclic estrogen and progestin therapy.
14. These adolescents are generally sterile and should be counseled regarding this aspect.
15. Uterine synechiae: This problem requires referral to a gynecologist for possible transhysteroscopic lysis of the adhesions.

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).

1. Disordered eating: Physically active female adolescents and young adults may develop an energy deficit of calories that may either be unintentional, related to increased demands of training, or intentional in an attempt to lose weight or body fat for enhanced performance or appearance. Disordered eating behaviors may include restricting food intake, bingeing and/or purging by vomiting, laxative use, diuretics, and diet pills. These individuals may also develop compulsive exercise behaviors. Disordered eating behaviors may impair athletic performance, increase risk of injury, and increase the risk of menstrual dysfunction and loss of BMD.
2. Menstrual dysfunction: Menstrual dysfunction in athletes may include primary amenorrhea, secondary amenorrhea, oligomenorrhea, and luteal phase deficiency. Menstrual dysfunction is more common in athletes than in the general population. Athletes, particularly runners, gymnasts, and dancers, with secondary amenorrhea may fall into either the hypothalamic-pituitary dysfunction or the hypothalamic-pituitary failure category.
3. Decreased BMD: There is evidence to suggest that athletes with amenorrhea have low levels of estrogen and may be at risk for osteoporosis and stress fractures (Cann et al., 1984;Drinkwater et al., 1986; Marcus et al., 1985). Some studies suggest that when amenorrhea

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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):

1. Most bone mineralization in female adolescents occurs by the middle of the second decade of life.
2. Premature bone demineralization occurs in young women with hypothalamic dysfunction that manifests as either amenorrhea or oligomenorrhea in the setting of participation in athletics or dance, and eating disorders.
3. Regular menses and fertility should return with a decrease in the intensity of activity. An adolescent with significant menstrual dysfunction attributed to exercise should be encouraged to increase her caloric intake and modify excessive exercise activity.
4. Calcium intake should be increased to 1,500 mg/day in these young women.
5. Hormonal therapy: If the teen does not respond to progesterone withdrawal or has a documented low circulating E₂level, estrogen and progesterone replacement therapy should be considered, particularly in amenorrheic athletes who show no signs of gaining weight or reducing activity after 6 months. These individuals may require higher doses of estrogen than replacement doses (1.25 mg/day of conjugated estrogen [Premarin], rather than 0.625 mg/day). However, controversy still exists regarding the beneficial effects on BMD in amenorrheic athletes, particularly those who are underweight. Conjugated estrogen, in doses that improve BMD in postmenopausal women and in combination with medroxyprogesterone, has not been shown to improve BMD in young women with anorexia nervosa (Klibanski et al., 1995). The role of oral medroxyprogesterone (10 mg/day, 10 days/month) in improving BMD in teenage girls with hypothalamic amenorrhea or oligomenorrhea also remains unclear, but preliminary data suggest that it may have negative effects on BMD (Hergenroeder et al., 1997). Some authorities have advocated the use of combination oral contraceptive pills in young women with hypothalamic amenorrhea. In addition, androgens, growth hormone, IGF-1 and bisphosphonates are the being used in clinical trials (Gordon, 1999; Gordon et al., 2002; Grinspoon et al., 2002; Miller et al., 2005; Golden et al., 2005).
6. The practitioner should evaluate these individuals, as outlined previously, to eliminate the possibility of pregnancy, thyroid dysfunction, prolactinoma, or a disorder of androgen excess. It should not be assumed that amenorrhea is simply secondary to exercise.

Polycystic Ovary Syndrome

Definition

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:

• Oligo and/or anovulation
• Clinical and/or biochemical signs of hyperandrogenism
• Polycystic ovaries by ultrasonography

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.

Etiology

Endocrine Findings

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:

1. Inappropriate gonadotropin secretion (IGS) characterized by the following:
2. Elevated serum LH level (>21 mIU/mL)
3. Reference-range or low FSH level
4. Exaggerated response of LH, not FSH, to GnRH
5. LH : FSH ratio often >3

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1. Elevated bioactive LH (generally a research tool, but even more sensitive for PCOS than an elevated immunoreactive LH level)
2. Steroid hormones
3. Estrone (E₁): Significantly elevated serum levels
4. E₂: Reference-range level of total E₂, but elevated unbound or free E₂level
5. Androstenedione and dehydroepiandrosterone sulfate (DHEAS): Elevated serum levels
6. Testosterone: Often minimally elevated serum levels are seen, with elevated free (unbound) testosterone
7. Source of excess androgens: The source may be secretion from the ovaries, the adrenal gland, or both, in women with a primary diagnosis of PCOS. Two other sources contribute to androgen excess:
8. Androstenedione is converted peripherally in adipose tissue to testosterone.
9. There is a decrease in binding of testosterone to sex hormone-binding globulin (SHBG). Healthy females have approximately 96% of their testosterone bound to SHBG, where it is inactive, whereas patients with PCOS have only 92% of their testosterone bound; therefore, there is a larger percentage of free and active testosterone in patients with PCOS.

Pathophysiology

The exact initiating cause of PCOS is not known but may be related to the following:

1. Abnormal hypothalamic-pituitary function
2. Abnormal ovarian function
3. Abnormal adrenal androgen metabolism
4. Insulin resistance: Insulin resistance may exist in both obese and lean women with PCOS and may promote the hyperandrogenic state

Factors leading to the development of PCOS include the following:

1. Insulin resistance at the time of puberty contributing to a relative hyperinsulinemic state
2. Insulin and IGF-1 have mitogenic effects on the ovaries, causing theca cell hyperplasia, which leads to excessive androgen production. Hyperinsulinemia has been directly correlated with a decrease in hepatic production of insulin-like growth factor–binding protein 1 (IGFBP1). The decrease in bound IGF-1 results in an increase in free IGF-1. The increase in IGF-1 and the decrease in IGFBP1 have both been found to correlate with increases in adrenal and ovarian androgens, resulting in the clinical presentation of premature adrenarche and PCOS (Ibanez et al., 1997; Silfen et al., 2002). Therefore, both high IGF-1 levels and low IGFBP1 levels may correlate with early insulin resistance and be pathophysiologically and clinically linked to the progression to PCOS and insulin resistance.
3. The increased ovarian androgen levels cause follicular atresia, impairing E₂production.
4. The E₁levels are elevated due to increased conversion of androstenedione to E₁ in adipose cells, which leads to suppression of FSH and tonic stimulation of LH, which further aggravate theca cell stimulation.
5. The combination of theca cell hyperplasia and arrested follicular maturation constitutes the typical histological features of PCOS.
6. Because not all adolescents ultimately develop PCOS, it is thought that there is a genetic factor involved. Genetic studies of family clusters have shown a high incidence of affected relatives (Legro, 1995). A dominant mode of inheritance seems most likely, but the type and degree of expression may vary within the same family. The syndrome may be transmitted through paternal or maternal sides of a family. Both the insulin receptor genes and the LH β-subunit gene have been mapped to chromosome 19. However, chromosomal studies of patients with PCOS have shown no consistent abnormality.

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.

Clinical Consequences

PCOS can present with many symptoms. Table 52.1 indicates the prevalence of various signs and symptoms associated with PCOS.

1. Anovulation: Anovulation is a key feature. Usually, the anovulation in PCOS is chronic and presents as either oligomenorrhea or amenorrhea of perimenarcheal onset. Some women who report normal menses may be anovulatory. Few women with PCOS have ovulatory function.
2. Polycystic ovaries: The ovaries in patients with PCOS are usually enlarged, pearly white, sclerotic with multiple (20 to 100) cystic follicles. Normally, follicles develop to approximately 19 to 20 mm and then ovulation occurs. In women with PCOS, multiple follicles develop, but only to approximately 9 to 10 mm in size. Histologically, the ovaries have the same number of primordial follicles, but the number of atretic follicles is doubled. Also, there is an absence of corpora lutea. The polycystic ovary is a sign, not a disease entity on its own. The typical histological changes of the polycystic ovary can be seen in ovaries of any size. A sonographic spectrum exists within patients with PCOS, and polycystic ovaries on ultrasound are not by themselves sufficient for diagnosis of PCOS.
3. Hyperandrogenism/hirsutism: Hyperandrogenism is a key feature of PCOS. Hyperandrogenism in PCOS is primarily ovarian in origin, although adrenal androgens may contribute. The development of hirsutism depends not only on the concentration of androgens in the blood but also on the genetic sensitivity of the hair follicles to androgens. Clinical hirsutism may not occur in all women with PCOS, but women with PCOS have elevated blood androgen levels.
4. Obesity: Originally, obesity was regarded as a classic feature, but its presence is extremely variable and not mandatory for diagnosis. Approximately 40% to 50% of women with PCOS are obese. Obesity in women with PCOS is usually of the android type, with increased

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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.

TABLE 52.1 Prevalence of Major Clinical Features of Polycystic Ovary Syndrome

Goldzieher and Axelrod (1963)a Balen et al. (1995)b Carmina and Lobo (1996)c a Compilation of data from 187 published studies. Polycystic ovary syndrome (PCOS) was diagnosed on the basis of clinical data and the laparoscopic diagnosis of polycystic ovaries. b Patients were diagnosed on the basis of ultrasonographic findings alone. c PCOS was diagnosed on the basis of hyperandrogenic chronic anovulation (unpublished data). From Lobo RA. Polycystic ovary syndrome. In: Lobo RA, Mishell DR, Shoupe D, et al. eds. Infertility, contraception and reproductive endocrinology. Malden, MA: Blackwell Science, 1997, with permission. No. of patients 1,079 1,741 240 Amenorrhea 51% 19.2% 16% Oligomenorrhea NR 47% 64% Polymenorrhea NR 2.7% 4% Normal menses 12% 29.7% 15% Hirsutism 69% 66.2% 70% Acne NR 34.7% 11.2% Obesity 41% 38.4% 43.7% Acanthosis nigricans — 2.5% 2.1%

5. Infertility: Although infertility is usually not of concern to the adolescent patient, the risk is significantly elevated due to anovulation.
6. Cancer risk: There is an increased risk for cancer of the endometrium due to prolonged unopposed estrogen stimulation of the endometrial lining from chronic anovulation. There may also be an increased risk of breast cancer associated with chronic anovulation during the reproductive years. The risk of endometrial cancer is increased threefold, and there may also be an increased risk of breast cancer in these women.
7. Elevated lipoprotein profile: The abnormalities in women with PCOS include elevated levels of cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C) and lower levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1. Although hyperandrogenism plays some role in these changes, hyperinsulinemia (insulin resistance) and increased inflammatory cytokines probably have a larger effect.
8. Insulin resistance and hyperinsulinemia: Both are well-recognized features of PCOS and associated with many of the late complications of PCOS (Lobo and Carmina, 2000). Approximately 50% of women with PCOS are insulin resistant. Although insulin resistance is associated with obesity, it can also be found in normal-weight women with PCOS. The cause-effect relationship between insulin and androgens in PCOS is still controversial and is under investigation. It has also been suggested that anovulation is a major factor associated with insulin resistance in women with PCOS. The exact pathogenesis of insulin resistance is not clear and may be related to excessive serine phosphorylation of the insulin receptor or downstream insulin signaling effects.
9. Impaired glucose tolerance and diabetes: Women with PCOS are at increased risk for impaired glucose tolerance and overt type 2 diabetes mellitus because of the insulin resistance. One study found that 31% of obese, reproductive-age women with PCOS had impaired glucose tolerance and 7.5% had overt diabetes (Legro et al., 1999). Even in the nonobese women with PCOS, 10.3% had impaired glucose tolerance and 1.5% had diabetes, three times the rate in the general population. Adolescents with PCOS have been found to be similarly at risk for insulin resistance and diabetes (Palmert et al., 2002).
10. Cardiovascular disease: Because of the prevalence of the risk factors listed previously, women with PCOS may be at long-term risk for increased cardiovascular disease. Adult women with PCOS have an estimated sevenfold risk of myocardial infarction (Lobo and Carmina, 2000). In addition, these young women can also have increased levels of plasminogen-activator inhibitor 1 (PAI-1), which inhibits fibrinolysis and is a risk factor for myocardial infarction (Ehrmann et al., 1997).

Differential Diagnosis

1. Familial hirsutism and/or increased sensitivity to normal androgen levels.
2. Androgen-producing ovarian and adrenal tumors: For further discussion, see Chapter 58 on hirsutism and virilism.
3. Cushing syndrome: Potential influence of Cushing syndrome is usually excluded by history and physical examination, and if needed, a 24-hour urine collection for free cortisol and an overnight dexamethasone suppression test can be done.
4. CAH: A mild 21-hydroxylase deficiency can mimic PCOS. The diagnosis of CAH is based on elevated morning serum 17-hydroxyprogesterone level, particularly after a 0.25-mg single-dose injection of adrenocorticotropic hormone.

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5. Stromal hyperthecosis: Stromal hyperthecosis probably represents a disorder related to PCOS. However, in this disorder, the testosterone levels are higher and may be as high as those in patients with androgen-producing tumors. These patients may be not only hirsute but also virilized. The history is one of slow-onset progression of symptoms and signs. Ovarian vein catheterization shows increased, but equal amounts, of testosterone from each ovary.

Diagnosis

Criteria for the diagnosis of PCOS include the following:

1. Irregular menses: Chronic anovulation with a perimenarcheal onset of menstrual irregularities.
2. Hyperandrogenism with or without skin manifestations: Biochemical or clinical evidence of androgen excess. Serum testosterone level is the best marker for ovarian causes of hyperandrogenism and DHEAS is the best marker of adrenal sources.
3. Absence of other androgen disorders (adrenal hyperplasia or tumor).

The following are not needed for diagnosis but are supportive evidence of the diagnosis:

1. Polycystic ovaries on ultrasonography (not required for diagnosis but extremely prevalent).
2. Increased body weight: Body mass index (BMI) >30 kg/m²in adults or >85th percentile in children.
3. Elevated LH and FSH levels: Although LH and FSH levels have been used widely, the sensitivity and specificity of these hormones are low.
4. Prolactin: Most individuals with PCOS have reference-range levels of prolactin, although 20% have mildly elevated levels (Luciano et al., 1984). Prolactin may augment adrenal androgen secretion in this subset of patients.

Therapy

Infertility

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.

Hirsutism

1. Cosmetic methods, including shaving, waxing, or electrolysis.
2. Oral contraceptives have some utility in 60% to 100% of women, but 6 to 12 months are required before noticeable differences are seen. Combination pills that contain low androgenic progestins such as norethindrone, norgestimate, or desogestrel should be used. Pills with antiandrogenic components (Yasmin) can also be considered (Guido et al., 2004).

Oral contraceptives work in the following manner:

1. Suppressing LH production and thereby reducing ovarian androgen production
2. Increasing the binding capacity of SHBG and thereby decreasing free testosterone production
3. Decreasing adrenal androgen production
4. Decreasing 5α-reductase activity

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.

Menstrual Irregularities

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

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.

Metabolic Changes

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

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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:

• Family history of type 2 diabetes in a first- or second-degree relative
• High-risk race/ethnicity (American Indian, African American, Hispanic, Asian/Pacific Islander)
• Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, PCOS) (American Diabetes Association, 2000).

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.

Web Sites

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.

References and Additional Readings

Adashi EY, Resnick CE, Ricciarella E, et al. Granulosa cell-derived insulin-like growth factor (IGF) binding proteins are inhibitory to IGF-I hormonal action: evidence derived from the use of a truncated IGF-I analog. J Clin Invest 1992;90:1593.

American Academy of Pediatrics, Committee on Sports Medicine and Fitness. Medical concerns in the female athlete. Pediatrics 2000;106:610.

American Diabetes Association. Type 2 diabetes in children and adolescents. American Diabetes Association. Pediatrics 2000;105:671.

Bachrach LK, Katzman DK, Litt IF, et al. Recovery from osteopenia in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 1991;72:602.

Baer JT. Endocrine parameters in amenorrheic and eumenorrheic adolescent female runners. Int J Sports Med 1993;14:191.

Baer JT, Taper LJ, Gwazdauskas FG, et al. Hormonal and metabolic factors affecting bone mineral density in adolescent amenorrheic and eumenorrheic female runners. J Sports Med Phys Fitness 1992;32:51.

Balen AH, Conway GS, Kaltsas G, et al. Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. Hum Reprod 1995;10:2107.

Baillargeon JP, Iuorno MJ, Nestler JE. Insulin sensitizers for polycystic ovary syndrome. Clin Obstet Gynecol 2003;46:325.

Brooks-Gunn J, Warren MP, Hamilton LH. The relation of eating problems and amenorrhea in ballet dancers. Med Sci Sports Exerc 1987;19:41.

Bullen BA, Skrinar GS, Beitins IZ, et al. Induction of menstrual disorders by strenuous exercise in untrained women. N Engl J Med 1985;312:1349.

Byrne J, Fears TR, Gail MH, et al. Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol 1992;1666:788.

Byrne J, Mulvihill JJ, Myers MH, et al. Effects of treatment on fertility in long-term survivors of childhood and adolescent cancer. N Engl J Med 1987;317:1315.

Calabrese LH, Kirkendall DT. Nutritional and medical considerations in dancers. Clin Sports Med 1983;2:539.

Cann CE, Martin MC, Genant HK, et al. Decreased spinal mineral content in amenorrheic women. JAMA 1984;251:626.

Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab1999;84:1897.

Carpenter SE. Psychosocial menstrual disorders: stress, exercise, and diet's effect on the menstrual cycle. Curr Opin Obstet Gynecol 1994;6:536.

Constantini NW, Warren MP. Menstrual dysfunction in swimmers: a distinct entity. J Clin Endocrinol Metab 1995;80:2740.

P.703

Copeland PM, Sacks NR, Herzog DB. Longitudinal follow-up of amenorrhea in eating disorders. Psychosom Med 1995;57:121.

Cumming DC, Strich G, Brunsting L. Amenorrheic joggers differ in hormone profile. Obstet Gynecol News 1982;17:12.

Cumming DC, Rebar RW. Exercise and reproductive function in women. Am J Ind Med 1983;4:113.

Davajan V. Primary amenorrhea. In: Mishell DR Jr, Davagan V, Lobo A, eds. Infertility, contraception, and reproductive endocrinology, 3rd ed. Boston: Blackwell Science, 1991.

Davajan V. Secondary amenorrhea. In: Mishell DR Jr, Davagan V, Lobo A, eds. Infertility, contraception, and reproductive endocrinology, 3rd ed. Boston: Blackwell Science, 1991.

Devereaux MD, Parr GR, Lachmann SM, et al. The diagnosis of stress fractures in athletes. JAMA 1984;252:531.

Drinkwater BL, Nilson K, Chesnut CH III, et al. Bone mineral content of amenorrheic and eumenorrheic athletes. N Engl J Med 1984;311:277.

Drinkwater BL, Nilson K, Ott S, et al. Bone mineral density after resumption of menses in amenorrheic athletes. JAMA 1986;256:380.

Dueck CA, Manore MM, Matt KS. Role of energy balance in athletic menstrual dysfunction. Int J Sport Nutr 1996;6:165.

Dunaif A. Insulin resistance and ovarian dysfunction. In: Moller DE, ed. Insulin resistance. New York: John Wiley and Sons, 1993:301.

Dunaif A, Graf M, Mandeli J, et al. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987;65:499.

Dunaif A, Green G, Futterweit W, et al. Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1990;70:699.

Dunaif A, Seqal KR, Shelley DR, et al. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 1992;41:1257.

Ehren EM, Mahour GH, Isaacs H Jr. Benign and malignant ovarian tumors in children and adolescents: a review of 63 cases. Am J Surg 1984;147:339.

Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005; 352:1223.

Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol 1997;82:2108.

Eliakim A, Beyth Y. Exercise training, menstrual irregularities and bone development in children and adolescents. J Pediatr Adolesc Gynecol 2003;16:201.

Emans SJ. The athletic adolescent with amenorrhea. Pediatr Ann 1984;13:605.

Emans SJ, Grace E, Hoffer FA, et al. Estrogen deficiency in adolescents and young adults: impact on bone mineral content and effects of estrogen replacement therapy. Obstet Gynecol 1990;76:585.

Evangelia Z, Erasmia K, Dimitrios L. Treatment options of polycystic ovary syndrome in adolescence. Pediatr Endo Rev 2006;3(Suppl 1):208.

Fagan KM. Pharmacologic management of athletic amenorrhea. Clin Sports Med 1998;17:327.

Fleming R, Hopkinson ZE, Wallace AM, et al. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab 2002;87:569.

Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333:853.

Frisch RE, Wyshak G, Vincent L. Delayed menarche and amenorrhea in ballet dancers. N Engl J Med 1980;303:17.

Goldzieher JW, Axelrod LR, Clinical and Biochemical Features of Polycystic Ovarian Disease. Fertil Steril 1963;14:631.

Guido M, Romualdi D, Giuliani M, et al. Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study. J Clin Endocrinol Metab 2004;89:2817.

Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update 2005;11:391.

Guido M, Romualdi D, Giuliani M, et al. Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study. J Clin Endocrinol Metab 2004;89:2817.

Glueck CJ, Wang P, Fontaine R, et al. Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS). J Adolesc Health2001;29:160.

Golden NH, Iglesias EA, Jacobson MS, et al. Alendronate for the treatment of osteopenia in anorexia nervosa: randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2005;90:3179.

Goodman LR, Warren MP. The female athlete and menstrual function. Curr Opin Obstet Gynecol 2005;17:466.

Gordon CM. Menstrual disorders in adolescents: excess androgens and the polycystic ovary syndrome. Pediatr Clin North Am 1999;46:519.

Gordon CM. Bone density issues in the adolescent gynecology patient. J Pediatr Adolesc Gynecol 2000;13:157.

Gordon CM, Grace E, Emans SJ, et al. Effects of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial. J Clin Endocrinol Metab2002;87:4935.

Greene JW. Exercise-induced menstrual irregularities. Compr Ther 1993;19:116.

Griffin JE, Edwards C, Madden JD, et al. Congenital absence of the vagina: clinical review. Ann Intern Med 1976;85:224.

Grinspoon S, Thomas L, Miller K, et al. Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa. J Clin Endocrinol Metab2002; 87:2883.

Grimes DA, Godwin AL, Rubin A, et al. Ovulation and follicular development associated with three low-dose oral contraceptives: a randomized controlled trial. Obstet Gynecol1994;83(1):29.

Gulekli B, Turhan NO, Senoz S, et al. Endocrinological, ultrasonographic, and clinical findings in adolescent and adult polycystic ovary patients: a comparative study. Gynecol Endocrinol 1993;7:273.

Hergenroeder AC. Bone mineralization, hypothalamic amenorrhea, and sex steroid therapy in female adolescents and young adults. J Pediatr 1995;126:683.

Hergenroeder AC, Smith EO, Shypailo R, et al. Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone or placebo over 12 months. Am J Obstet Metab Gynecol 1997; 176:1017.

Hintz RL. New approaches to growth failure in Turner syndrome. Adolesc Pediatr Gynecol 1989;2:172.

Hobart JA, Smucker DR. The female athlete triad. Am Fam Physician 2000;61:3357.

Holt VL, et al. Functional ovarian cysts in relation to the use of monophasic and triphasic oral contraceptives. Obstet Gynecol 1992;79:529.

Huffman JW, Dewhurst CJ, Capraro UJ, eds. Ovarian tumors in children and adolescents. In: The gynecology of children and adolescence, 2nd ed. Philadelphia: WB Saunders, 1981.

P.704

Ibanez L, Potau N, Zampolli M, et al. Hyperinsulinemia and decreased insulin-like growth factor-binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche. J Clin Endocrinol Metab 1997; 82:2283.

Ibanez L, Valls C, Marcos MV, et al. Insulin sensitization for girls with precocious pubarche and with risk for polycystic ovary syndrome: effects of prepubertal initiation and postpubertal discontinuation of metformin treatment. J Clin Endocrinol Metab 2004;89:4331.

Ibanez L, de Zegher F. Flutamide-metformin plus ethinylestradiol-drospirenone for lipolysis and antiatherogenesis in young women with ovarian hyperandrogenism: the key role of metformin at the start and after more than one year of therapy. J Clin Endocrinol Metab 2005; 90:39.

Iglesias EA, Coupey SM. Menstrual cycle abnormalities: diagnosis and management. Female Reprod Health Adolesc Med State Art Rev 1999;10:255.

Imai A, Furui T, Tamaya T. Gynecologic tumors and symptoms in childhood and adolescence: 10-years' experience. Int J Gynaecol Obstet 1994;5:227.

Isojarvi JIT, Laatikainen TJ, Pakarinen AJ, et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993;329:1383.

Jacobs HS. Polycystic ovary syndrome: etiology and management. Curr Opin Obstet Gynecol 1995;7:203.

Jansen RP. Ovulation and the polycystic ovary syndrome. Aust N Z J Obstet Gynaecol 1994;34:277.

Johnson C, Powers PS, Dick R. Athletes and eating disorders: the National Collegiate Athletic Association study. Int J Eat Disord 1999;26:179.

Jonnavithula S, Warren MP, Fox RP, et al. Bone density is compromised in amenorrheic women despite return of menses: a 2-year study. Obstet Gynecol 1993;81:669.

Kahn JA, Gordon CM. Polycystic ovary syndrome. Adolesc Med 1999;10:321.

Klibanski A, Biller BM, Schoenfeld DA, et al. The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa. J Clin Endocrinol Metab 1995; 80:898.

Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393.

Lane DE. Polycystic ovary syndrome and its differential diagnosis. Obstet Gynecol Surv 2006;61:125.

Lanes SF, Birmann B, Walker AM, et al. Oral contraceptive type and functional ovarian cysts. Am J Obstet Gynecol 1992; 166:95.

Laughlin GA, Yen SS. Nutritional and endocrine-metabolic aberrations in amenorrheic athletes. J Clin Endocrinol Metab 1996;81:4301.

Laughlin GA, Yen SS. Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. J Clin Endocrinol Metab 1997;82:318.

Legro RS. The genetics of polycystic ovary syndrome. Am J Med 1995;98:9S.

Legro RS, Kunselman AR, Dodson WC, et al. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;84:165.

Lindberg JS, Fears WB, Hunt MM, et al. Exercise-induced amenorrhea and bone density. Ann Intern Med 1984;101:647.

Lindberg JS, Powell MR, Hunt MM, et al. Increased vertebral bone mineral in response to reduced exercise in amenorrheic runners. West J Med 1987;146:39.

Lint VS, Auletta F, Kathpalia S. Gonadal function in women with chronic renal failure: a study of the hypothalamic-pituitary axis. Proc Clin Dial Transplant Forum (Washington)1977;7:39.

Lobo RA. Polycystic ovary syndrome. In: Mishell DR Jr, Davajan V, eds. Infertility, contraception, and reproductive endocrinology. Oradell, NJ: Medical Economics Books, 1986.

Lobo RA, Carmina E. The importance of diagnosing the polycystic ovary syndrome. Ann Intern Med 2000;132:989.

Luciano AA, Chapler FK, Sherman BM. Hyperprolactinemia in polycystic ovary syndrome. Fertil Steril 1984;41:719.

Lutter JM, Cushman S. Menstrual patterns in female runners. Phys Sportsmed 1982;10:60.

Mantzoros CS. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;351:987.

McGowan L. Adnexal masses: a visual guide. Female Patient 1989;14:48.

McKenna TJ. Pathogenesis and treatment of polycystic ovary syndrome. N Engl J Med 1988;318:558.

Marcus R, Cann C, Madvig P, et al. Menstrual function and bone mass in elite women distance runners. Ann Intern Med 1985;102:158.

Marshall LA. Clinical evaluation of amenorrhea in active and athletic women. Clin Sports Med 1994;13:371.

Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician 2006;73:1374.

Micklesfield LK, Lambert EV, Fataar AB. Bone mineral density in mature, premenopausal ultramarathon runners. Med Sci Sports Exerc 1995;27:688.

Miller KK, Grieco KA, Klibanski A. Testosterone administration in women with anorexia nervosa. J Clin Endocrinol Metab 2005;90:1428.

Moghetti P, Castello R, Negri C, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85:139.

Mooradian AD, Morley JE. Endocrine dysfunction in chronic renal failure. Arch Intern Med 1984;144:351.

Morin-Papunen L, Rautio K, Ruokonen A, et al. Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab2003;88:4649.

Morin-Papunen LC, Vauhkonen I, Koivunen RM, et al. Endocrine and metabolic effects of metformin versus ethinyl estradiolcyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab 2000; 85:3161.

Moshang T, Holsclaw DS. Menarchal determinants in cystic fibrosis. Am J Dis Child 1980;134:1139.

Nader S. Polycystic ovary syndrome and the androgen-insulin connection. Am J Obstet Gynecol 1991;165:346.

Neinstein LS. Menstrual dysfunction in pathophysiologic states. West J Med 1985;143:476.

Neinstein LS. Menstrual problems in adolescents. Med Clin North Am 1990;74:1181.

Neinstein LS, Castle GE. Congenital absence of the vagina. Am J Dis Child 1983;137:669.

Neinstein LS, Stewart D, Wang CI, et al. Menstrual dysfunction in cystic fibrosis. J Adolesc Health Care 1983;4:153.

Nestler JE. Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Semin Reprod Endocrinol 1997;15(2):111.

Okano H, Mizunuma H, Soda M. Effects of exercise and amenorrhea on bone mineral density in teenage runners. Endocrinol Jpn 1995;42:271.

P.705

Olson BR. Exercise-induced amenorrhea. Am Fam Physician 1989;39:213.

Otis CL, Drinkwater B, Johnson M, et al. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc 1997;29:i.

Palmert MR, Gordon CM, Kartashov AI, et al. Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:1017.

Pasloff ES, Slap GB, Pertschuk MJ, et al. A longitudinal study of metacarpal bone morphometry in anorexia nervosa. Clin Orthop 1992;278:217.

Patterson DE. Menstrual dysfunction in athletes: assessment and treatment. Pediatr Nurs 1995;21:310.

Pletcher JR, Slap GB. Menstrual disorders. Amenorrhea. Pediatr Clin North Am 1999;46:505.

Polaneczky MM, Slap GB. Menstrual disorders in the adolescent: amenorrhea. Pediatr Rev 1992;13:43.

Porcu E, Venturoli S, Prato LD, et al. Frequency and treatment of ovarian cysts in adolescence. Arch Gynecol Obstet 1994; 255:69.

Poretsky L, Piper B. Insulin resistance, hypersecretion of LH, and a dual-defect hypothesis for the pathogenesis of polycystic ovarian syndrome. Obstet Gynecol 1994;84(4):613.

Puffer JC. Athletic amenorrhea and its influence on skeletal integrity. Bull Rheum Dis 1994;43:5.

Putukian M. The female athlete triad. Clin Sports Med 1998; 17:675.

Rencken ML, Chesnut CH III, Drinkwater BL. Bone density at multiple skeletal sites in amenorrheic athletes. JAMA 1996;276:238.

Richardson GS, Scully RE, Niktui N, et al. Common epithelial cancers of the ovary (two parts). N Engl J Med 1985;312: 415.

Rodin A, Thakkar H, Taylor N, et al. Hyperandrogenism in polycystic ovary syndrome. N Engl J Med 1994;330:460.

The Rotterdam E/A. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41.

Russell JB, Mitchell D, Musey PI, et al. The relationship of exercise to anovulatory cycles in female athletes: hormonal and physical characteristics. Obstet Gynecol 1984a;63:452.

Sanborn CF, Horea M, Siemers BJ, et al. Disordered eating and the female athlete triad. Clin Sports Med 2000;19:199.

Schwartz B, Rebar RW, Yen SSC. Amenorrhea and long distance running. Fertil Steril 1980;34:306.

Seino S, Seino M, Bell GI. Human insulin-receptor gene. Diabetes 1990;39:129.

Shalet SM. Effects of cancer chemotherapy on gonadal function of patients. Cancer Treat Rev 1980;7:141.

Shangold MM. How I manage exercise-related menstrual disturbances. Phys Sportsmed 1986;14:113.

Siegel ML, Surratt IT. Pediatric gynecologic imaging. Obstet Gynecol Clin North Am 1992;19:103.

Silfen ME, Manibo AM, Ferin M, et al. Elevated free IGF-I levels in prepubertal Hispanic girls with premature adrenarche: relationship with hyperandrogenism and insulin sensitivity. J Clin Endocrinol Metab 2002;87:398.

Singh KB. Menstrual disorders in college students. Am J Obstet Gynecol 1981;140:299.

Solomon CG. The epidemiology of polycystic ovary syndrome: prevalence and associated disease risks. Endocrinol Metab Clin North Am 1999;28:247.

Spanos WJ. Preoperative hormonal therapy of cystic adnexal masses. Am J Obstet Gynecol 1973;116:551.

Speroff L, Glass RH, Kase NG. Amenorrhea. In: Speroff L, Glass, RH, Kase NG, eds. Clinical gynecologic endocrinology and infertility, 4th ed. Baltimore: Williams & Wilkins, 1989:165.

Speroff L, Shangold MM, Dale E. Impact of exercise on menstruation and reproduction. Contrib Gynecol Obstet 1982; 19:54.

Stager JM, Ritchie-Flanagan B, Robertshaw D. Reversibility of amenorrhea in athletes. N Engl J Med 1984;310:51.

Stillman RJ, Schinfeld JS, Schiff I. Ovarian failure in long term survivors of childhood malignancy. Am J Obstet Gynecol 1981; 139:62.

Trent ME, Rich M, Austin SB, et al. Quality of life in adolescent girls with polycystic ovary syndrome. Arch Pediatr Adolesc Med 2002;156:556.

Trent ME, Rich M, Austin SB, et al. Fertility concerns and sexual behavior in adolescent girls with polycystic ovary syndrome: implications for quality of life. J Pediatr Adolesc Gynecol 2003;16(1):33.

Tweedy A. Polycystic ovary syndrome. J Am Acad Nurse Pract 2000;12:101.

Velazquez EM, Mendoza S, Hamer T, Sosa F and Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647.

Vigersky RM, Andersen AE, Thompson RN, et al. Hypothalamic dysfunction in secondary amenorrhea associated with simple weight loss. N Engl J Med 1977;297:1141.

Warren MP. The effects of exercise on pubertal progression and reproductive function in girls. J Clin Endocrinol Metab 1980;51:1150.

Warren MP, Jewelewicz R, Dyrenfurth I, et al. The significance of weight loss in the evaluation of pituitary response to LHRH in women with secondary amenorrhea. J Clin Endocrinol Metab 1975;40:601.

Warren-Ulanch J, Arslanian S. Treatment of PCOS in adolescence. Best Pract Res Clin Endocrinol Metab 2006;20:311.

Watson RE, Bouknight R, Alguire PC. Hirsutism: evaluation and management. J Gen Intern Med 1995;10:283.

Waxman J. Chemotherapy and the adult gonad: a review. J R Soc Med 1983;76:144.

Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;35:987.

West RV. The female athlete: the triad of disordered eating, amenorrhea and osteoporosis. Sports Med 1998;26:63.

Winer-Muram MT, Emerson DE, Muram D, et al. The sonographic features of the peripubertal ovaries. Adolesc Pediatr Gynecol 1989;2:160.

Yurth EE. Female athlete triad. West J Med 1995;162:149.