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Previous Volume 328:1297-1301 May 6, 1993 Number 18 Next

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ABSTRACT

Background 17-Ketosteroid reductase deficiency results in male pseudohermaphroditism because conversion of the weak androgen androstenedione to the more potent androgen testosterone is impaired. If a late-onset form exists, hypogonadism and gynecomastia caused by decreased testosterone production and increased estrogen production, respectively, would be expected as the major clinical manifestations in men.

Methods We studied 48 male subjects, ranging from 14 to 26 years of age, who had idiopathic pubertal gynecomastia. Serum concentrations of gonadal and adrenal steroid hormones were measured before and after the administration of corticotropin and after the combined administration of chorionic gonadotropin and dexamethasone for three days.

Results We identified three unrelated subjects (ages, 16, 17, and 26 years) with results indicative of a partial deficiency of testicular 17-ketosteroid reductase. The three subjects had gynecomastia as well as decreased libido and impotence. Their mean (±Sd) base-line serum androstenedione and estrone concentrations were elevated as compared with the levels in the 45 subjects without this enzyme deficiency (androstenedione, 380 ±70 vs. 110 ±70 ng per deciliter [13 ±2 vs. 4 ±2 nmol per liter]; estrone, 138 ±12 vs. 46 ±9 pg per milliliter [511 ±44 vs. 170 ±33 pmol per liter]). After the administration of chorionic gonadotropin, the mean serum androstenedione concentration in these three subjects was 910 ±48 ng per deciliter (32 ±2 nmol per liter) and the mean serum estrone concentration was 260 ±16 pg per milliliter (962 ±59 pmol per liter). The mean serum testosterone concentration at base line was 210 ±80 ng per deciliter (7.4 ±2.8 nmol per liter) in the 3 subjects, as compared with a value of 410 ±12 ng per deciliter (14.4 ±0.42 nmol per liter) in the 45 other subjects, and it did not increase in response to the administration of chorionic gonadotropin. The concentrations of androstenedione and estrone in spermatic venous serum were 19 times higher and 73 times higher, respectively, than in normal men. The serum concentrations of follicle-stimulating hormone and luteinizing hormone in these three subjects were inappropriately low, suggesting the presence of hypogonadotropic hypogonadism.

Conclusions A late-onset form of testicular 17-ketosteroid reductase deficiency can cause gynecomastia and hypogonadism in men.

The final step in the synthesis of sex hormones in the gonads is the conversion of androstenedione to testosterone and of estrone to estradiol, reactions that are catalyzed by 17-ketosteroid reductase. Deficiency of 17-ketosteroid reductase is a rare cause of inherited male pseudohermaphroditism² and has been also described as a cause of micropenis³ and polycystic ovary disease^4,5. A partial deficiency of this enzyme was considered the cause of gynecomastia in one man,⁶ and we recently suggested that some adolescent boys with varicocele also have a partial deficiency⁷. Biochemically, this deficiency is characterized by marked overproduction of androstenedione and estrone and decreased production of testosterone and estradiol, so that the ratios of androstenedione to testosterone and of estrone to estradiol in serum are high, both basally and after the administration of chorionic gonadotropin⁸. Since gynecomastia is a prominent clinical manifestation in patients with 17-ketosteroid reductase deficiency after puberty,^2,9,10,11 we suspected that some men with gynecomastia might have a mild form of this enzyme deficiency. Among 48 adolescents and young men with gynecomastia, we found 3 unrelated male subjects who also had decreased libido and gonadal steroid values in peripheral and spermatic venous serum indicative of a partial deficiency of testicular 17-ketosteroid reductase. Therefore, we conducted studies of hypothalamic pituitary-testicular function in these three subjects.

Methods

Subjects

We studied testicular function in 48 male subjects, ranging from 14 to 26 years of age, who had gynecomastia of unknown cause. All had breast development of at least Tanner stage 3, pubic-hair development of stage 4 to 5, and total testicular volumes between 20 and 30 ml (normal [±SD], 20 ±5)¹². Their mean (±SD) body-mass index (the weight in kilograms divided by the square of the height in meters) was 20 ±2 (normal, 20 to 24.5). Persons with varicoceles were excluded from the study. The histories and physical examinations of the 48 subjects were otherwise unremarkable.

Three of these subjects (ages, 16, 17, and 26 years), who were unrelated, had biochemical evidence of a partial deficiency of testicular 17-ketosteroid reductase, on the basis of findings of supranormal ratios of androstenedione to testosterone and of estrone to estradiol in serum at base line and after the administration of chorionic gonadotropin. In addition to gynecomastia, these three subjects had had decreased libido and impotence for two to three years. One of them had a six-year-old sister and a nine-year-old brother who had premature adrenarche. All three subjects were of normal height and weight, with normal body proportions and body-hair growth. Their external genitalia were normal, as was testicular volume (mean, 26 ±5 ml). Semen analyses were not done. None had any clinical or laboratory evidence of renal or hepatic disease. All had normal findings on chest films, computed tomography of the adrenal glands, ultrasonography of the testicles, and magnetic resonance imaging of the brain and testes. They all had a 46,XY karyotype. None of the other 45 men had a family history of gynecomastia, abnormal pubertal development, or hypogonadism.

This study was approved by the institutional human review committee, and written consent was obtained from all study subjects.

Endocrine Studies

Basal serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, androstenedione, estrone, estradiol, and dehydroepiandrosterone were measured in all 48 subjects. All also underwent corticotropin-stimulation tests, in which cosyntropin was administered intravenously at a dose of 0.25 mg at 8 a.m.; serum levels of 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone, estradiol, and cortisol were measured before and 60 minutes after the administration of corticotropin. In addition, the 48 subjects were given dexamethasone, at a dose of 0.5 mg orally every six hours, for 10 days and chorionic gonadotropin, at a daily dose of 3000 IU intramuscularly, on days 7, 8, and 9. Blood samples were collected at 8 a.m. on days 7 and 10. One month later, the three subjects with results suggestive of 17-ketosteroid reductase deficiency underwent a clomiphene-stimulation test, followed a week later by a gonadotropin-releasing hormone-stimulation test. Clomiphene citrate was administered orally for seven days at a daily dose of 100 mg. Serum LH and FSH concentrations were measured on days 0, 3, 5, and 7, and serum concentrations of testosterone, androstenedione, estrone, and estradiol were measured on days 0 and 7. Serum FSH and LH concentrations were also measured before the intravenous administration of 100 µg of gonadotropin-releasing hormone and every 20 minutes thereafter for a total of 120 minutes.

To rule out the possibility of an estrogen-secreting tumor, the base-line serum concentrations of androgens and estrogens were measured in the right and left spermatic veins of these three subjects.

Laboratory Measurements and Statistical Analysis

Serum steroid hormone concentrations were determined by radioimmunoassay after extraction and celite-microcolumn chromatography, according to previously described methods^13,14,15. Serum LH and FSH concentrations were measured by radioimmunoassays that conformed to the National Institutes of Health standard LER-907.

Statistical significance was estimated with the multiple-range test of Kramer¹⁶. The results are presented as means ±SD.

Results

The steroid profiles of the 3 subjects with 17-ketosteroid reductase deficiency and the other 45 subjects with gynecomastia are shown in Table 1. At base line, the three subjects with 17-ketosteroid reductase deficiency had elevated serum androstenedione and estrone concentrations, moderately elevated levels of serum dehydroepiandrosterone, and lower than expected concentrations of serum testosterone, as compared with the other subjects. The serum estradiol, 17-hydroxyprogesterone, and cortisol concentrations were similar in the two groups. The base-line ratios of androstenedione to testosterone (1.8 ±0.8 vs. 0.2 ±0.18) and of estrone to estradiol (3.4 ±0.9 vs. 0.9 ±0.1) in serum were higher in the subjects with 17-ketosteroid reductase deficiency than in the subjects with pubertal gynecomastia.

View this table: [in this window] [in a new window]   Table 1. Serum Androgen and Estrogen Concentrations in 3 Subjects with Gynecomastia Due to 17-Ketosteroid Reductase Deficiency and 45 Men with Idiopathic Pubertal Gynecomastia at Base Line, after a Corticotropin-Stimulation Test, and after Treatment with Dexamethasone and Chorionic Gonadotropin.

 
The nine-year-old brother of one of the three subjects, who had premature adrenarche, also had elevated serum concentrations of androstenedione (298 ng per deciliter [10.4 nmol per liter]), dehydroepiandrosterone (580 ng per deciliter [20.3 nmol per liter]), and estrone (80 pg per milliliter [296 pmol per liter]) associated with low serum concentrations of testosterone (5 ng per deciliter [0.17 nmol per liter]) and estradiol (10 pg per milliliter [36.7 pmol per liter]) and slightly elevated serum LH and FSH concentrations (10 and 12 mIU per milliliter, respectively). The markedly elevated ratios of androstenedione to testosterone (59.6) and of estrone to estradiol (8.0) in this boy's serum indicated the presence of 17-ketosteroid reductase deficiency, suggesting the disorder had a genetic basis in this family.

In the three subjects with 17-ketosteroid reductase deficiency, the serum androstenedione and estrone concentrations did not increase after the administration of corticotropin and were not suppressed by dexamethasone. The administration of chorionic gonadotropin with dexamethasone resulted in an increase in the serum concentration of androstenedione (to 910 ±4 ng per deciliter [32 ±2 nmol per liter]) and estrone (to 260 ±16 pg per milliliter [962 ±59 pmol per liter]), but no change in the serum testosterone concentration. In contrast, the other subjects with pubertal gynecomastia had a twofold to threefold increase in serum testosterone concentrations after the administration of chorionic gonadotropin.

The serum steroid hormone concentrations in the spermatic veins of the three men are shown in Table 2. The mean serum concentration of androstenedione (58,600 ±1700 ng per deciliter [2051 ±59 nmol per liter]) was nearly 20 times higher than that in normal men¹⁷ and 3 times higher than that of testosterone. The mean serum testosterone concentration was approximately one fourth of the value in normal men. The mean spermatic venous serum estrone concentration was more than 70 times normal and 3.6 times higher than that of estradiol. The mean serum estradiol concentration was approximately 4.5 times higher than normal.

View this table: [in this window] [in a new window]   Table 2. Serum Androgen and Estrogen Concentrations in the Spermatic Veins of Three Subjects with Late-Onset 17-Ketosteroid Reductase Deficiency.

 
The three subjects had base-line serum concentrations of FSH (1.8 ±0.5 mIU per milliliter) and LH (1.2 ±0.3 mIU per milliliter) that were inappropriately low for their serum testosterone concentrations, suggesting the presence of hypogonadotropic hypogonadism (Table 3). However, their serum LH and FSH concentrations increased substantially in response to the administration of the antiestrogen clomiphene citrate (peak serum LH level, 71.2 ±6.5 mIU per milliliter; peak serum FSH level, 22.0 ±5.1 mIU per milliliter), and these increases were accompanied by increases in the serum concentrations of androstenedione (959 ±110 ng per deciliter [34 ±4 nmol per liter]) and estrone (310 ±28 pg per milliliter [1147 ±104 pmol per liter]). In contrast, the serum testosterone and estradiol concentrations increased very little (peak levels, 340 ±28 ng per deciliter [11.9 ±1.0 nmol per liter] and 58 ±13 pg per milliliter [213 ±48 pmol per liter], respectively). Serum concentrations of LH and FSH increased from 1.8 ±0.5 and 1.5 ±0.3 mIU per milliliter to peak values of 8.8 ±2.8 and 5.7 ±1.0 mIU per milliliter, respectively, after the administration of gonadotropin-releasing hormone (data not shown).

View this table: [in this window] [in a new window]   Table 3. Serum Hormonal Responses to the Administration of Clomiphene Citrate in Three Subjects with 17-Ketosteroid Reductase Deficiency.

 
Discussion

17-Ketosteroid reductase is an essential enzyme for the production of testosterone in testicular tissue. A congenital deficiency of this enzyme is characterized by inadequate production of testosterone by the fetal testes and therefore incomplete masculinization of the external genitalia¹⁸. In fact, at birth most patients have either female external genitalia or such marked ambiguity of the genitalia that they are raised as girls. At puberty, however, virilism occurs in patients with this disorder, leading often to adoption of a male sex role^19,20. Although most previously described patients had ambiguous genitalia,^2,19,20,21 reports of an infant with 17-ketosteroid reductase deficiency who had a male phenotype, micropenis, and undescended testes and of partial 17-ketosteroid reductase deficiency in a male subject with isolated gynecomastia⁶ and in some women with polycystic ovary disease^4,5 suggested that there may be a late-onset, nonclassic form of testicular 17-ketosteroid reductase deficiency analogous to the nonclassic forms of congenital adrenal hyperplasia.

The hormonal hallmarks of 17-ketosteroid reductase deficiency are elevated serum androstenedione and estrone concentrations and low serum testosterone concentrations. Gynecomastia and hypogonadism, therefore, would be expected to be the major clinical manifestations. Among a group of adolescents and young men with idiopathic gynecomastia, we found three unrelated subjects with hormonal patterns both at base line and after dynamic testing that suggested the presence of a mild form of testicular 17-ketosteroid reductase deficiency. These three subjects had elevated serum androstenedione and estrone concentrations and low serum testosterone concentrations, as well as large increases in serum androstenedione and estrone but little increase in serum testosterone and estradiol after the administration of chorionic gonadotropin. The base-line ratios of androstenedione to testosterone and of estrone to estradiol in serum were therefore increased, and they increased further after the administration of chorionic gonadotropin, indicating decreased testicular 17-ketosteroid reductase activity. Furthermore, the concentrations of androstenedione and estrone in the spermatic venous serum were markedly increased.

The conversion of estrone to estradiol is more normal than the conversion of androstenedione to testosterone in this disorder^9,21,22,23. Our three patients had increased testicular production of both estrogens, but the increased ratio of estrone to estradiol in these patients clearly indicates that 17-ketosteroid reductase activity in the estrogen pathway was impaired. The high serum estrone and estradiol concentrations in the spermatic effluent were probably due to enhanced testicular aromatase activity. Since many other disorders associated with hyperestrogenism in men are not associated with 17-ketosteroid reductase deficiency, it is unlikely that the impaired enzyme activity was due to an inhibitory effect of estrogens on the activity of this enzyme.

The marked increase in serum dehydroepiandrosterone concentrations in the three subjects after the administration of chorionic gonadotropin, as well as the high concentrations in the spermatic veins, supports the concept that dehydroepiandrosterone rather than 17-hydroxyprogesterone is probably responsible for the increased production of androstenedione^24,25. However, in contradistinction to most patients with 17-ketosteroid reductase deficiency who have male pseudohermaphroditism, the subjects had no abnormality in sexual development. The finding of normal male phenotypes in these subjects indicated that testicular 17-ketosteroid reductase activity was normal during embryogenesis; presumably its activity decreased sometime thereafter. At puberty, an inability to increase testosterone production normally would lead to an increase in the secretion of gonadotropin (as reported in most other cases), which in turn would induce Leydig-cell hyperplasia, with overproduction of androstenedione and estrone.

In time, the secretion of estrone might become independent of gonadotropin secretion, and the hyperestrogenemia might inhibit the secretion of gonadotropin, thus explaining the low serum LH and FSH concentrations in the three subjects. The occurrence of estrogen-mediated suppression of gonadotropin secretion is supported by the large increase in serum LH and FSH concentrations that was observed after the administration of clomiphene, an antiestrogen. Similarly, the poor serum LH and FSH response to gonadotropin-releasing hormone was probably due to the negative-feedback effect exerted by the increased secretion of estrone. The hypogonadotropic hypogonadism in these subjects, therefore, was most likely a secondary event.

The proper care of patients with 17-ketosteroid reductase deficiency is uncertain. Agents that decrease the production or action of estrogen would be expected to ameliorate gynecomastia -- if the patient desires treatment for that problem -- but not hypogonadism; mastectomy thus seems a better treatment. Testosterone therapy would ameliorate the symptoms of hypogonadism and decrease the secretion of estrogen, to the extent that such secretion is gonadotropin-dependent, but it would also be expected to decrease spermatogenesis, if present. However, it is likely that spermatogenesis is severely and irreparably impaired as a result of both the abnormal testicular production of steroid and decreased secretion of FSH.

In conclusion, we have demonstrated the existence of a late-onset form of 17-ketosteroid reductase deficiency in men with clinical and laboratory findings suggestive of hypogonadotropic hypogonadism and hyperestrogenism. The disorder is presumably congenital, but could be acquired. The finding of 3 subjects with this deficiency among 48 subjects with gynecomastia suggests that this disorder may be more common than expected.

Source Information

From the Division of Pediatric Endocrinology and Genetics, Winthrop-University Hospital, Mineola, N.Y., and the Health Science Center, State University of New York at Stony Brook, Stony Brook.

Address reprint requests to Dr. Castro-Magana at the Division of Pediatric Endocrinology, Winthrop-University Hospital, 107 Mineola Blvd., Mineola, NY 11501.

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