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Development Of 5aReductase Inhibitors

As discussed, although other approaches to androgen ablation and androgen inhibition (antiandrogens) have been evaluated in the past, these methods produced only a moderate desired impact and had many side effects, thus limiting their use (14). Typical antiandrogen (e.g., flutamide) side effects include onset of erectile dysfunction, impairment in libido and ejaculation, gastrointestinal distress, nausea, flatulence, gynecomastia, breast pain, diminished energy levels, impairment in spermatogenesis, and decreased muscle mass. In contrast, because mature (postpubertal) patients with 5 a-reductase deficiency did not appear to have impaired sexual function or diminished external mascu-linization, the 5 a-reductase enzyme was a logical target for treating men with clinically significant BPH. The potential blockade of 5a-reductase seemed to provide hope for decreasing prostate growth and minimizing side effects.

Diagnosis Of Klinefelters Syndrome

KS in a prepubertal boy are verbal learning disabilities and taurodontism, the unusual enlargement of the pulp of the tooth seen roughly half of men and boys with KS (46). After puberty, individuals with KS will often exhibit tall stature (usually greater than 184 cm) with proportionally long legs and will frequently manifest an arm span that is greater than their height (51). In adults, the diagnosis of KS should be considered in men with gynecomastia, primary hypogonadism, infertility, or osteoporosis. Because serum testosterone levels may be normal, serum gonadotropins should also be measured. Peripheral blood karyotyping can be used to confirm the diagnosis, although this test can be negative in mosaic individuals, and tissue karyotype may be necessary (9).

Androgen Replacement Therapy

Testosterone therapy results in a more male phenotype, with increases in facial and pubic hair, muscle size and strength, libido, and bone mineral density, and improved mood (21,47,52,53). We recommend testosterone therapy beginning at the time of puberty to allow boys with KS to experience pubertal changes in tandem with their peers. In addition, this approach may allow for optimal enhancement of bone mineral density. Even if testosterone therapy is delayed until adulthood, it is still associated with beneficial improvements in mood, behavior, and sense of well-being (53). Testosterone therapy has no beneficial effect on infertility or gynecomastia, which is best treated with surgical resection if bothersome.

Devices used in corrective surgeries during adolescence

In males, gynecomastia is a common condition that occurs during adolescence and usually regresses spontaneously within 1 year, but moderate to severe cases that do not resolve may undergo reduction mammoplasty surgery for cosmetic and psychological sequelae. While surgery in the past has used open excision techniques, newer liposuction technology has been used with the aim of avoiding large areas of scarring and nerve and vessel injury. Ultrasound-assisted liposuction (UAL) has been recently used to treat gynecomastia in both adolescent and adult males. UAL selectively destroys adipose

Other Potential Causes of Androgen Deficiency

Men with pre-existing testicular dysfunction (including renal failure) may be more susceptible to further impairment of steroidogenesis caused by medications or illnesses. HMG-CoA reductase inhibitors inhibit cholesterol synthesis and may, therefore, impair steroidogenesis, particularly because adverse events consistent with androgen deficiency (gynecomastia and impotence) have been reported. A prospective, open-label study of 25 nephrotic, hyperlipidemic men with moderate chronic renal failure treated for 12 mo with lovastatin (40 mg d) showed no change in baseline and GnRH-stimulated LH, FSH, and testosterone levels (38). A more discerning test of testicular steroidogenesis, such as testosterone response to submaximal hCG stimulation, was not reported. Adrenal steroidogenesis (plasma cortisol before and after adrenocor-ticotropic hormone ACTH stimulation) was comparable with age-matched healthy controls at entry and remained unchanged by lovastatin treatment. Not surprisingly,...

Potassium Sparing Diuretics

Hyperkalemia (increase in potassium in the blood), a serious event, may be seen with the administration of potassium-sparing diuretics. Hyperkalemia is most likely to occur in patients with an inadequate fluid intake and urine output, those with diabetes or renal disease, the elderly, and those who are severely ill. In patients taking spironolactone, gynecomastia (breast enlargement in the male) may occur. This reaction appears to be related to both dosage and duration of therapy. The gynecomastia is usually reversible when therapy is discontinued, but in rare instances, some breast enlargement may remain.

Management Of Delayed Puberty

For boys who are hypogonadal, testosterone substitution therapy should be initiated at a low dose, because too large a dose may advance skeletal maturation disproportionately and, thus, compromise final adult height. Furthermore, large doses may cause acne, gynecomastia, or too-rapid change in libido. Doses are adjusted according to the clinical response (Tanner stage and bone age). Most commonly, long-acting testosterone preparations, which are administered intramuscularly, are used for this purpose. Esterification of testosterone with either propionic or enanthic acid at position 17 prolongs the metabolite's activity (69). Testosterone propionate is not a suitable testosterone preparation for substitution therapy, because plasma concentration show wide fluctuations, and the maximal between-injection interval is only 3 d with a 50 mg dose (70). Testosterone enanthate at a dose of 250 mg intramuscularly has a half-life of 4.5 d. Based on multiple-dose pharmacokinetics, an injection...

Congenital Idiopathic Hypogonadotropic Hypogonadism CIHH Definition

Delayed Adolescence

Most often, however, the diagnosis of CIHH is delayed until adolescence. At that time, considerable clinical heterogeneity is observed with variable spontaneous puber-tal development. The most common phenotype is represented by patients who fail to undergo puberty (see Fig. 4). Their clinical features include a lack of secondary sex characteristics, eunuchoidal body proportions (upper lower body ratio < 1 with an arm span > 6 cm standing height) (44,45), a high-pitched voice, slight anemia, delayed bone age, and prepubertal sized testes (1-3 mL). A large proportion of these subjects report a history of cryptorchidism (40 ) or microphallus (20 ) (46). These latter two clinical signs provide evidence for the lack of activity of the hypothalamic-pituitary-gonadal axis during the feto-neonatal window and, thus, represent clinical surrogate markers of the failure to activate GnRH secretion at that stage of development. However, both of these markers lack sensitivity, because other...

Clinical Features Of Klinefelters Syndrome

Klinefelter Syndrome

An individual with Klinefelter's syndrome. Note tall body proportions, gynecomastia, relative paucity of facial and body hair, and small testis. (Photos courtesy of Dr. C. Alvin Paulsen.) Fig. 2. An individual with Klinefelter's syndrome. Note tall body proportions, gynecomastia, relative paucity of facial and body hair, and small testis. (Photos courtesy of Dr. C. Alvin Paulsen.) of puberty do not progress normally. This leads to the classic phenotype of KS long legs, with an arm span frequently greater than height, gynecomastia, decreased muscle mass and increased abdominal adiposity, decreased facial and body hair, and small testes which often measure less than 5 mL in volume (see Fig. 2). The penis may be decreased in size but is often of normal length. Gynecomastia is variable but is often prominent and may require surgical correction. Mosaicism may present more subtly, because affected individuals can appear anywhere along a phenotypic spectrum between classical KS and...

Pathophysiology Of Klinefelters Syndrome

Testicular Biopsy Klinefelter

The pathophysiology of KS-related gynecomastia is also not entirely clear. Individuals with KS do exhibit mildly elevated plasma levels of estradiol, probably from increases in peripheral aromatization and decreased clearance. However, histologic analysis of breast tissue from individuals with KS demonstrates intraductal hyperplasia rather than the ductal hyperplasia seen in high estrogen states in the male, such as cirrhosis (18).

Spermatogenesis Stimulation

Testosterone And Prenatal Development

Terone production and the synthesis of other Leydig cell products that are required for spermatogenesis and testicular growth. With a dose of 1000-2500 IU twice per week (e.g., Monday and Friday), serum testosterone levels usually normalizes within 1-2 mo, otherwise, the dose is increased. Higher doses of hCG also increase plasma estradiol levels, however, and may cause gynecomastia. The development of anti-hCG antibodies is rare but may be considered if there is resistance to GnRH therapy (23). Both intramuscular and sc adminstration of hCG are effective. Intramuscular administration is often more painful and may require medical paramedical assistance for injections. Compliance is greater when the sc route of administration is chosen, as this can be done by self-injection comparable to insulin injection in patients with diabetes. Treatment With hCG and Human Menopausal Gonadotropin. hMG is purified from the urine of menopausal women. The usual starting dose is 75 IU three times...

Proscar Longterm Efficacy And Safety Study

No difference in the incidence of serious adverse events between the two groups was observed. In fact, the only adverse effects that were drug-related and for which the incidence was greater than or equal to 1 and greater than placebo were symptoms of sexual dysfunction (impotence, decreased libido, decreased ejaculate volume, ejaculation disorder), breast enlargement tenderness, and rash. Interestingly, two cases of breast cancer were diagnosed in the placebo group neither man had an antecedent history of gynecomastia. No cases of breast cancer were detected in the finasteride group during the study.

Hypogonadism Can Result From Defects at Several Levels

To establish the cause(s) of reproductive dysfunction, physical examination and medical history, semen analysis, hormone determinations, hormone stimulation tests, and genetic analysis are performed. Physical examination should establish whether eunuchoidal features (i.e., infantile appearance of external genitalia and poor or absent development of secondary sex characteristics) are present. In men with adult-onset reproductive dysfunction, physical examination can uncover problems such as cryptorchidism (nondescendent testes), testicular injury, varicocele (an abnormality of the spermatic vasculature), testicular tumors, prostatic inflammation, or gynecomastia. Medical and family history help determine delayed puberty, anosmia (an inability to smell, often associated with GnRH dysfunction), previous fertility, changes in sexual performance, ejacula-tory disturbances, or impotence (an inability to achieve or maintain erection).

Historical Description Of Klinefelters Syndrome

Klinefelter, Jr., a native of Baltimore and a graduate of the Johns Hopkins Medical School, spent a year working as a traveling fellow with Dr. Fuller Albright in the Metabolic Ward of the Massachusetts General Hospital in Boston (3). At that time, Dr. Albright was at the height of his formidable academic career and, among many other subjects, was interested in the endocrinology of sexual development and the therapeutic applications of the recently available steroid hormones. Dr. Albright had identified a group of adult men with a previously unchar-acterized syndrome typified by gynecomastia, small testes, and varying degrees of eunuchoidism. Dr. Albright assigned Dr. Klinefelter the task of further describing this syndrome for publication. Klinefelter, Albright, and their colleague Dr. Edward Reifenstein, Jr. published their description of the syndrome in a classic article in The Journal of Clinical Endocrinology in 1942 (4). In this article, they described a cohort...

Other Possible Adverse Effects

Increased oiliness of skin and acne are common complaints after testosterone treatment, especially if high doses of testosterone are used. These conditions can be treated by topical measures, the testosterone dose can be reduced, or the testosterone preparation can be changed. Because testosterone esters and native testosterone are aromatized to estrogens, changes in the androgen to estrogen balance may occur after testosterone replacement, which may cause gynecomastia. Testosterone replacement also causes fluid retention during the early weeks of treatment and should be used with caution in older patients with congestive heart failure or poor myocardial function.

Androgen Deficiency

Men with chronic renal failure exhibit features consistent with classical androgen deficiency reproductive manifestations, including gynecomastia, impotence, testicular atrophy, impaired spermatogenesis, and infertility, as well as somatic disorders of bone, muscle, and other androgen responsive tissues (1,2). However, only a single well-controlled study has examined androgen replacement therapy in men with uremia (34). Nineteen men who were receiving regular hemodialysis were randomized to receive either oral testosterone undecanoate (240 mg d) or placebo for 12 wk. Libido and sexual activity were increased, but hemoglobin was unchanged. There were no adverse clinical effects or hepatotoxicity. Effects on bone, muscle, cognition, and well-being were not reported. Further studies examining physiological androgen replacement therapy in men with chronic renal failure, notably using nonparenteral therapies in view of the increased bleeding risks in men with chronic renal failure, would...

Breast

Prolactin normally stimulates breast tissue growth, differentiation, and lactation. Gynecomastia (breast enlargement) and galactorrhea (lactation) are expected consequences of antipsychotic-induced hyperprolactinemia in both men and women, although the actual risk of breast-related side effects is not well delineated (Schreiber and Segman 1997). Estimates of the frequency of galactorrhea in women treated with typical antipsychotics vary, with reports of up to half of premenopausal women experiencing galactorrhea, but this side effect is rarely reported in men (Ghadirian et al. 1982 Gitlin 1994 Inoue et al. 1980 Windgassen et al. 1966). One of the few studies to date that has systematically inquired about breast changes naturalistically followed 150 women with schizophrenia treated for 75 days with a variety of typical antipsychotics (Windgassen et al. 1996). Nineteen percent (28 150) of the women admitted to galactorrhea. The mean prolactin value for these patients was 55 ng mL, but 4...

Transdermals

In addition to testosterone gels, the potent androgen DHT gel has been studied as a treatment for hypogonadal younger (94) and older men (95-98). DHT improved sexual dysfunction in older partially androgen-deficient men but had minimal effect on muscle mass and strength (95,96). It is controversial whether DHT has significant benefits over testosterone as an androgen replacement therapy. DHT is not converted to estradiol (nonaromatizable androgen). Because some of the beneficial (and adverse effects) of testosterone have been attributed, at least in part, to its metabolite estradiol, it is not clear whether DHT will have a positive effect on bone mass, cognitive function, and fat mass (99) or be free from the problem of testosterone-induced gynecomastia.

Leydig Cell Tumors

Leydig Cell Testosterone

LCTs are found at all ages from 2 to 90 yr, with a peak occurrence in the fifth decade of life. In boys, these tumors typically occur between the ages of 4 and 10 yr and account for approx 10 of cases of precocious puberty (122). They are uniformly benign hormonally active tumors that present with macrogenitosomia (a syndrome that is characterized by precocious enlargement of the genitals), including an enlarged phallus and or prostate, and premature growth of pubic hair (120). Adult men with LCTs often present with a painless testicular mass, usually associated with gynecomastia, infertility, decreased libido, and other feminizing features. Gynecomastia is bilateral in 90 of the cases (123,124). LCTs secrete both androgenically and estrogenically active steroids. Unlike normal Leydig cells, androgen secretion by the tumor is in independent of pituitary control. LCTs have an abnormally high aromatase activity and secrete E2 (125). The resulting elevated E2 and decreased, or low-normal...

Endemic Mycoses

Coccidioides Mycosis

Both androgenic and corticosteroid hormones, causing decreased libido and gynecomastia and, rarely, Addison's disease. Itraconazole does not have these effects when given at recommended doses but does cause edema, hypokalemia, and hypertension in a small percentage of patients. All of the azole agents have been noted to cause hepatitis in a small number of patients.

Clinical Correlates

Visualizing Nondisjunction

The clinical features of Klinefelter syndrome, found only in males and usually detected at puberty, are sterility, testicular atrophy, hyalinization of the seminiferous tubules, and usually gynecomastia. The cells have 47 chromosomes with a sex chromosomal complement of the XXY type, and a sex chromatin body (Barr body formed by condensation of an inactivated sex chromosome a Barr body is also present in normal females) is found in 80 of cases (Fig. 1.11). The incidence is approximately 1 in 500 males. Nondisjunction of the XX homologues is the most common causative event. Occasionally, patients with Klinefelter syndrome have 48 chromosomes 44 autosomes and four sex chromosomes (XXXY). Although mental retardation is not generally Figure 1.11 Patient with Klinefelter syndrome showing normal phallus development but gynecomastia (enlarged breasts).

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