Therapy for amenorrhea should be directed at the underlying cause. If out-flow obstruction or Asherman syndrome is present, surgical consultation with a gynecologist is needed. For ovarian failure secondary to gonadal dysgenesis with a Y chromosome or fragment, surgical removal of the gonads at the time of diagnosis has been recommended because of the high risk of gonad-related malignancy. In androgen insensitivity syndrome, removal of the gonads may be deferred until immediately after pubertal maturation because the risk of malignancy appears to be low until after puberty [16]. Psychological counseling is also needed in patients with gonadal dysgenesis and androgen insensitivity syndromes.

Management of TS is complex and focuses on recognizing and monitoring the associated anomalies [17]. About 30% of patients with TS have congenital heart
defects (e.g., bicuspid aortic valve and coarctation of the aorta), and 30% have renal anomalies. The risk of death from aortic aneurysm is high (relative risk [RR] of 63.23, with a 95% confidence interval [CI] of 20.48-147.31), and an initial evaluation with periodic echocardiography and follow-up by a cardiologist are needed [18]. Thyroid disease, usually Hashimoto disease, may occur in up to 30% of affected patients; therefore, TSH levels should be measured every 1 to 2 years or if symptoms suggestive of thyroid disease develop. Short stature can be improved significantly with the early use of growth hormone, and consideration for use should be given if and when the height is less than the 5th percentile or as indicated based on specific clinical features [13, 19]. Estrogen use will cause fusion of the epiphyses and may therefore limit final adult height (AH), depending on the total length of growth hormone therapy before starting estrogen [20]. However, starting growth hormone early may allow the use of estrogen at age 12 or 13 without compromising height gain [21]. Early use of estrogen may have some benefit on motor and nonverbal function in girls with TS [22], although this must be reconciled with the goal of increasing height. Bone-density studies should be done in adults and periodically thereafter [17]. Patients with TS, particularly primarily those with mosaicism, may rarely conceive spontaneously, though the outcomes of pregnancy often include chromosomal abnormalities, congenital anomalies, and fetal loss [23, 24]. The potential for pregnancy does not improve with medical interventions [25]. Ovum donation has allowed successful pregnancy outcomes in many women with Turner syndrome, but it is critical to detect somatic abnormalities, particularly cardiac disease, before embarking on a course of assisted fertility. Cyclic hormone replacement therapy (HRT) is justified by recent studies that suggest a beneficial effect of estrogen therapy on bone density and fracture risk in such patients [26, 27, 28, 29, 30, 31].

Nonsecretory pituitary tumors and tumors producing growth hormone or ACTH (Cushing syndrome) tumors may require surgical therapy, whereas the majority of prolactin-secreting tumors may be managed medically with dopamine agonist therapy. Treatment of adrenal hyperplasia consists of replacement glucocorticoid to suppress ACTH and hence adrenal androgen production while avoiding excessive steroid levels, which may cause growth retardation. In extremely rare situations with poor response to medical therapy, adrenalectomy may be required. A recent evidence-based guideline has been published and should be consulted for detailed therapy [32]. Ovarian and adrenal tumors are treated surgically. PCOS therapy is discussed in the section on hirsutism.

Hypothalamic dysfunction should be treated by addressing the underlying cause wherever possible. Weight gain in patients with anorexia may help normalize reproductive function and bone density [33, 34]. HRT is often initiated to optimize bone development in the setting of hypothalamic dysfunction, but results have been inconsistent [35]. More recent studies find that hormone replacement alone does not improve bone density, whereas weight gain and/or the administration of recombinant IGF-1 may lead to improvement both in markers of bone formation and in bone density [35, 36]. Baseline leptin, IGF-1, and androgen levels are predictive of bone microarchitecture, independent of body mass index (BMI) [37]. Nutritional counseling as well as psychological counseling may be necessary, and modification of exercise regimens may be helpful.

Table 5.1 is a summary of amenorrhea.

Goals of therapy include:

Lifestyle changes are recommended to encourage weight loss if the patient is overweight. Appropriate diet and exercise programs should be instituted in such patients and can be effective in controlling these disorders, including the associated hirsutism [55]. In obese PCOS patients, wieght loss with or without exercise may improve clinical manifestations; as little as 5-10% weight loss may often result in significant improvement. Weight loss is the best intervention for diabetes prevention and should be the first line of therapy for all obese PCOS. In women with PCOS and morbid obesity, gastric bypass should be considered.

Nonpharmacologic therapy for hirsutism includes hair removal by shaving, depilatories, bleaching, waxing, and photothermolysis. Topical ornithine decarboxylase inhibitors that theoretically slow hair growth by inhibiting an essential step in hair formation within the hair follicle may also be effective [56], but the terminal hairs typically reappear within a few weeks after cessation of the drug. Hormonal contraception, combined estrogen and progestin formulations, is the most effective therapy for hyperandrogenism and menstrual irregularities. The mechanisms of action of oral contraceptives include: (1) suppression of ovarian androgen production: (2) increasing SHBG (sex hormone binding globulin) which reduces bioavailable free testosterone; and (3) the direct anti-androgenic activity of some progestins such as cyproterone and drosperinone [57]. The combination pill ethinyl estradiol/drospirenone is Food and Drug Administration (FDA)-approved for the treatment of moderate to severe acne. The effective contraception from hormonal contraception allows for the addition of other antiandrogen medications that are contraindicated in pregnancy. Since antiandrogenic compoounds including spironolactone, cyproterone and others are dangerous to a developing make fetus, they are contraindicated during pregnancy. Therefore, effective contraception using OCPs may allow the safe introduction of additional anti-androgens if clinically necessary.

Antiandrogens antagonize the binding of testosterone and other androgens to the androgen receptor. Spironolactone is an antiandrogen that inhibits testosterone binding at the receptor level. It is rated as pregnancy category C by the U.S. FDA. In a review of six small, randomized, controlled trials, a significant benefit was noted after 6 months of taking spironolactone, 100 mg/d, compared with placebo [59]. The effects of spironolactone on hirsutism are at least comparable with those of flutamide and finasteride [60]. Spironolactone is often combined with an oral contraceptive pills (OCP) to help prevent pregnancy, to maintain regular menstrual cycles, and to augment therapeutic efficacy. Cyproterone acetate is a progestin that acts as an antiandrogen and is frequently used worldwide for hirsutism, but it is not available in the United States. Other antiandrogens and some OCPs have been demonstrated to be as effective as cyproterone acetate in most studies [61]. Flutamide is an antiandrogen that inhibits testosterone binding at the receptor level. It is FDA category D for pregnancy. It is as effective as spironolactone and finasteride in treatment of hirsutism [62]. Use of this agent in hirsutism should be limited to investigational studies because of the lack of improved efficacy, the potential for hepatic toxicity, the high cost, and its potential for fetal harm.

Finasteride inhibits 5α-reductase, which controls the conversion of testosterone to dihydrotestosterone. Although it is specific for the enzyme type found in the prostate, it has clinical effects on decreasing hair growth as well. It is FDA category X for pregnancy, showing fetal risk, and is therefore contraindicated in pregnancy and in women at risk for pregnancy. For hirsutism, it is slightly less effective in most studies compared with spironolactone and flutamide, although it may provide additional improvement in combination with some antiandrogenic OCPs [59, 62]. Side effects are minimal and the associated use of an oral contraceptive is mandatory. The effective dosage in women is 2.5 to 5 mg taken once daily.

Finasteride has some efficacy in the treatment of androgenic alopecia [63].

For all patients with precocious puberty, it is important to provide the child and family with professional counseling services, although no formal studies have been reported with clinical outcomes. Patients with isolated premature thelarche or premature adrenarche should be examined periodically to ensure that precocious puberty is not developing. Girls with premature adrenarche should be monitored especially for development of the PCOS and the insulin-resistance syndrome. Treatment of pseudoprecocious puberty must be directed at the underlying disease. Surgery, irradiation, and chemotherapy options exist for tumors causing precocious puberty. Aromatase inhibitors may be used for gonadotropinindependent precocious puberty [72, 73].

Treatment of boys with familial male-limited precocious puberty with spironolactone and testolactone helps controls symptoms of acne, erectile function, and aggression but without a significant improvement of predicted final adult height (AH) [74]. Activation of the central axis with development of CPP in response to circulating sex hormones limits the usefulness of this combination alone. Combination of spironolactone and testolactone with a GnRH agonist to prevent the activation of the central axis is more effective, with an improvement in final predicated AH [75]. The use of combination therapy with bicalutamide, an antiandrogen, and a third-generation aromatase inhibitor (anastrozole or letrozole) has been shown to reduce virilization, reduce bone age acceleration, and allow continued linear growth [76, 77].

In a small study, resistant cases may respond to ketoconazole [78].

No unanimity exists about treatment of CPP. Treatment goals include the preservation of the potential for normal AH, prevention of premature sexual activity, improvement of psychosocial problems related to the disorder, and prevention of early menarche [79]. Proposed criteria for therapy with GnRH agonists are as follows: patients that clearly meet the definition for precocious puberty with documentation of an active GnRH axis by GnRH stimulation testing or sleep studies
and sex hormone levels in the pubertal range with limited predicted adult height (PAH) (<5th percentile) or significant psychosocial problems from menses or early development [80]. Generally, therapy is initiated in very young children to prevent sexual development and in older children when bone-maturation acceleration outpaces linear growth velocity, resulting in premature closure of the epiphyses and diminished final AH. No studies document the benefits of gonadotropin releasing hormone (GnRH) therapy on ultimate psychosocial well-being in children with this disorder. Quality-of-life issues should enter into therapy considerations but must be individualized and have not been well studied. Long-term safety issues pertaining to the use of GnRH agonists are largely unknown. A review of earlier trials of GnRHa use suggests that therapy should be started before age 8 years to have a significant impact [79]. Therapy with GnRHa generally produces a height increase of 3 to 8 cm over that in untreated patients but typically 1 to 7 cm below the normal PAH. Newer studies suggest that a final AH appropriate for midparental height prediction is achieved by 85% to 90% of patients. Although some studies suggest that weight gain may be associated with therapy with GnRH analogues [81, 82], two recent large trials of GnRH therapy in 121 girls over 1 year revealed that GnRH therapy did not reverse the accretion of bone mass nor did obesity occur. Body composition and later menstrual function were normal and progression to PCOS was not observed [83, 84].

Addition of growth hormone in small studies has generally shown significantly improved heights in girls [85, 86, 87] but has not been clearly shown to have value in boys, although sample sizes in the studies have been small. Larger, more recent studies suggest a therapeutic benefit with a gain between pretreatment predicted adult height (PAH) and final height (FH) of 8.2 ± 4.8 cm according to tables for accelerated girls and 12.7 ± 4.8 cm according to tables for average girls in patients treated with GH plus GnRHa. In patients treated with GnRH alone, the gain calculated between pretreatment PAH for accelerated girls was just 2.3 ± 2.9 cm and 7.1 ± 2.7 cm greater than pretreatment PAH for average girls. The difference between the gain obtained in the two groups (˜6 cm) remained the same however the PAH was calculated [88]. The most powerful predictors of a good response are early age of disease, early age at therapy, rapidity of bone advancement, and initial predicted height to target height deficit [89]. The use of different assessment tools for evaluation of current bone age may be important in determining those children who would most benefit from the combination of GnRH analogues and growth hormone [90].