Precocious puberty

Administration of clomiphene may result in vasomotor flushes (which are like the hot flashes of menopause), abdominal discomfort, ovarian enlargement, blurred vision, nausea, vomiting, and nervousness. HCG administration may result in headache, irritability, restlessness, fatigue edema, and precocious puberty (when given for cryptorchism). 

Headache, edema, irritability, fatigue, nervousness, restlessness, precocious puberty, gynecomastia Vasomotor flushes, breast tenderness, abdominal discomfort, blurred vision, ovarian enlargement, nausea, vomiting, nervousness Same as glucocorticoids (Display 50-2)... 

In leukemia, the intensified use of methotrexate and glucocorticoids is responsible for causing an increased frequency of neurotoxicity and, in older children and adults, avascular necrosis of bone. High cumulative doses of anthracyclines can cause cardiomyopathy. Cranial irradiation causes neuropsychologic deficits and endocrine abnormalities that lead to obesity, short stature, precocious puberty, and osteoporosis.3 As newer and more intensive treatments enter clinical trials, close observation for long-term side effects will assume even greater importance.24... 

There are a variety of constitutively active mutations in the gene encoding the LH receptor. These variants result in gonadotropin-independent disorders such as testotoxicosis and familial male precocious puberty (FMPP) (91). These disorders are inherited in an autosomal dominant, male-limited pattern (92,93). 

Testotoxicosis is a form of male precocious puberty. The disorder results from a constitutive activation of the G a protein (reviewed in Chapter 6). This results in LH receptor activation that is analogous to the LH receptor mutant phenotypes. The disorder often presents alongside paradoxical pseudohypoparathyroidism type la (PHP-Ia), a condition that is marked by resistance to hormones acting through cAMP (PTH and TSH) (91). 

Molecular studies explained this apparent paradox when the temperature-sensitive G a Ala366Ser mutation of the G a protein was identified. At 32°C, the G a 366Ser mutation results in the constitutive cAMP accumulation that causes the testosterone secretion that is the hallmark of the testotoxicosis phenotype. At 37°C, however, the G a 366Ser mutation results in loss of adenylyl cyclase signaling, causing PHP-Ia. As a result, a single mutation that performs differently in different tissues causes precocious puberty and abnormalities of PTH and TSH (91). 

Familial Male Precocious Puberty and Constitutive LH Receptor Mutants... 

Latronico, A. C., Anasti, J., Amhold, 1. J., et al. (1995) A novel mutation of the luteinizing hormone receptor gene causing male gonadotropin-independent precocious puberty. J. Clin. Endocrinol. Metab. 80, 2490-2494. 

Kosugi, S., Van Dop, C., Geffner, M. E., et al. (1995) Characterization of heterogeneous mutations causing constitutive activation of the luteinizing hormone receptor in famdial male precocious puberty. Hum. Mol. Genet. 4, 183-188. 

The combination of spironolactone (2 mg/kg/day) and testolactone (20 to 40 mg/kg/day) for 6 months or more may be effective for short-term treatment of familial male precocious puberty. 

Extreme clinical examples of androgen excess include central precocious puberty, the adrenogenital syndromes, and androgen-secreting adrenal, ovarian, or testicular tumors. Less severe problems include idiopathic hirsutism, premenstrual syndrome, and severe cystic acne. 

GnRH analogues (see Chapter 59) can induce chemical castration by suppressing the pulsatile release of LH and FSH, hence inhibiting testicular steroidogenesis. Administration of these compounds reduces circulating testosterone levels. These compounds are inhaled, injected subcutaneously, or implanted subcutaneously. They are used in males in the treatment of precocious puberty and carcinoma of the prostate. 

Adverse effects include menstrual irregularities, deepening of voice in women, edema, cholestatic jaundice, virilization, priapism, increased libido, acne, precocious puberty, premature epiphyseal closure, gynaecomastia and hepatic carcinoma and reduction in spermatogenesis. 

It is used in menorrhagia, gynaecomastia, fibrocystic breast disease, treatment of visually proven endometriosis or symptomatic control when surgery is contraindicated. It is also used in infertility in women and precocious puberty in boys. 

It has a potent antiandrogen and mild progestional activity. It can also inhibit gonadotropin secretion in larger dose and also suppresses spermatogenesis and Leydig cell function. It is used in precocious puberty in males, acne, carcinoma prostate and hirsutism and virilization in women. 

Indications Management of endometriosis and treatment of central precocious puberty... 

Dosage form Two versions of Synarel are available Synarel Nasal Solution for Central Precocious Puberty and Synarel Nasal Solution for Endometriosis. They appear to be the same except for package and labeling. Each 0.5 ounce bottle contains 8 ml Synarel Nasal Solution 2mg/ml (as nafarelin base). Each bottle is supplied with a metered spray pump that delivers 200 pg of nafarelin per spray. 

B. Indications and use Lupron Injection, Lupron Depot, Lupron Depot-3 Month, and Lupron Depot-4 Month are indicated in the palliative treatment of advanced prostate cancer. These products offer an alternative treatment when orchiectomy or estrogen administration is either not indicated or unacceptable to the patient. Lupron Injection Pediatric and Lupron Depot-PED are indicated in the treatment of children with central precocious puberty. Lupron Depot and Lupron Depot-3 Month are indicated for the management of endometriosis, including pain relief and reduction of endometriotic lesions. 

Recommended dosage and monitoring requirements According to Micromedex, the effective doses of Lupron in prostate cancer are 1 mg subcutaneously daily, or in the depot formulation 7.5 mg intramuscularly (IM) monthly, 11.25 mg every 3 months, or 30 mg every 4 months. Lupron Depot-3 month 22.5 mg is used in the treatment of advanced prostate cancer. In endometriosis, the effective dose is 3.75mg depot IM monthly or 11.25mg every 3 months for 6 months. In central precocious puberty, the recommended starting dose of Lupron Injection Pediatric is 50pg/kg... 

G. Other applications Limited data show some beneficial effects of leuprolide in the treatment of breast cancer. According to Micromedex, there is good documentation that leuprolide is effective for bowel pain and nausea associated with irritable bowel syndrome. Leuprolide has been used for controlled ovarian hyperstimulation to enhance the in vitro fertilization-embryo transfer procedure. In endometriosis, the goal of treatment is pain relief and reduction of endometriotic lesions. In children with central precocious puberty, stimulated and basal gonadotropins are reduced to prepubertal levels. Testosterone and estradiol are reduced to prepubertal levels in males and females, respectively. 

G. Other applications Goserelin is useful for in vitro fertilization and is possibly effective in controlling precocious puberty and early puberty. Goserelin may promote fibroid regression, but rapid regrowth results upon discontinuation. 

Management of endometriosis or treatment of central precocious puberty (CPP) (gonadotropin-dependent precocious puberty) in children of both sexes... 

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