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Original Article

A Novel Testis-Stimulating Factor in Familial Male Precocious Puberty

List of authors.
  • Penelope K. Manasco, M.D.,
  • Mary E. Girton, R.T.,
  • Richard L. Diggs,
  • John L. Doppman, M.D.,
  • Penelope P. Feuillan, M.D.,
  • Kevin M. Barnes, B.S.,
  • Gordon B. Cutler, Jr., M.D.,
  • D. Lynn Loriaux, M.D., Ph.D.,
  • and Barry D. Albertson, Ph.D.

Abstract

Background.

Familial male precocious puberty is a gonadotropin-independent form of precocious puberty that occurs only in males. The cause of the disorder is unknown. To examine the hypothesis that the plasma of boys with familial male precocious puberty contains a novel stimulator of testicular testosterone production, we developed a bioassay using adult male cynomolgus monkeys.

Methods.

We collected plasma from 12 boys with familial male precocious puberty, 7 normal prepubertal boys of similar ages and with similar plasma gonadotropin levels, and 1 boy with hypogonadotropic hypogonadism and infused it into the testicular artery of adult male cynomolgus monkeys that had been pretreated with gonadotropin-releasing—hormone antagonist to inhibit the endogenous secretion of gonadotropins. Testicular venous effluent was collected at 15-minute intervals for 3 or 5 hours for the measurement of testosterone.

Results.

The mean (±SE) peak testosterone response, as compared with base line, was significantly greater in the monkeys infused with plasma from the 12 boys with familial male precocious puberty than in the monkeys infused with plasma from the 7 normal prepubertal boys and the boy with hypogonadotropic hypogonadism (385±51 vs. 184±25 percent, P<0.005) in the three-hour studies. Plasma from 92 percent of the boys with familial male precocious puberty and 12.5 percent of the normal prepubertal boys stimulated a response greater than 195 percent of base-line values. In the animals studied for five hours after receiving a second dose of antagonist, the mean peak testosterone response, as compared with base line, was significantly greater in the monkeys infused with plasma from three boys with familial male precocious puberty than in the monkeys infused with plasma from three normal prepubertal boys (363±81 vs. 115±6 percent, P<0.01). The mean area under the testosterone-response curve was significantly larger in the monkeys infused with plasma from the boys with familial male precocious puberty in the five-hour studies (154±34 vs.— 58±10 percent, P<0.005), but not in the three-hour studies.

Conclusions.

These findings support the presence of a circulating testis-stimulating factor in the plasma of boys with familial male precocious puberty. The production of such a factor would explain the biologic nature of the disorder. (N Engl J Med 1991; 324:227–31.)

Introduction

FAMILIAL male precocious puberty is a gonadotropin-independent form of isosexual precocity. The disease is transmitted in an autosomal dominant manner, although spontaneous cases do occur. Boys with the condition usually present with rapid growth and onset of secondary sexual characteristics at approximately three years of age. Adult men with the disorder are fertile, although there is some question about whether they have premature gonadal failure.

Schedewie et al.1 reported in 1981 that plasma from subjects with a familial form of precocious puberty characterized by Leydig-cell hyperplasia did not stimulate testosterone secretion from rat Leydig cells. They concluded that this condition was gonadotropin-independent. Subsequent studies2 3 4 confirmed the lack of measurable gonadotropins in serum and revealed a prepubertal serum gonadotropin response to stimulation with gonadotropin-releasing hormone (GnRH) and no change in testosterone secretion in response to the administration of a long-acting GnRH agonist. This evidence supports the conclusion that this form of precocious puberty is gonadotropin-independent. Recently, however, a luteinizing-hormone-like factor was detected in the plasma of boys with familial male precocious puberty with use of a murine Leydig-cell assay.5 The diverse responses in assays using Leydig cells from different species suggest that patients with this disorder might produce a species-specific testis-stimulating factor. This possibility prompted us to develop a bioassay for testosterone-stimulating activity in adult cynomolgus monkeys and to examine the hypothesis that the plasma of boys with familial male precocious puberty contains a novel stimulator of testicular testosterone production. In this article, we report data indicating that 11 of 12 such boys had a factor in their plasma that stimulated monkey testes to secrete testosterone.

Methods

Subjects

Table 1. Table 1. Clinical Features and Plasma Hormone Values in 12 Boys with Familial Male Precocious Puberty and 7 Normal Boys.*

We studied 12 boys (including one pair of brothers) with familial male precocious puberty (Table 1). All the boys had a family history of early puberty in at least one other close male relative (i.e., father, grandfather, or uncle). Central precocious puberty was excluded on the basis of prepubertal serum gonadotropin responses to GnRH and the absence of nocturnal luteinizing-hormone pulses characteristic of GnRH-dependent puberty. Other causes of GnRH-independent precocious puberty were excluded by the measurement of plasma 17-hydroxyprogesterone, 11-deoxycortisol, and chorionic gonadotropin levels and by ultrasonography of the testes and adrenal glands. Each boy's height was measured 10 times with a Harpenden stadiometer. Bone age was determined from radiographs of the left wrist and hand according to the method of Greulich and Pyle.6 Six of the boys were taking no medication at the time of the study. Two boys were taking testolactone, three were taking a combination of testolactone and spironolactone,7 and one was being treated with the GnRH agonist D-Trp6-Pro9-N-Et—luteinizing-hormone—releasing hormone.8

Seven normal prepubertal boys served as control subjects. The ages and plasma gonadotropin concentrations of these boys were similar to those of the boys with familial male precocious puberty. A 16-year-old boy with hypogonadotropic hypogonadism who was receiving treatment with parenteral testosterone was also studied to control for the high plasma testosterone concentrations characteristic of boys with familial male precocious puberty. His plasma concentration of luteinizing hormone was 4.1 IU per liter; of follicle-stimulating hormone, 6.6 IU per liter; and of testosterone, 9.2 nmol per liter. As a positive control for the bioassay, a 3-ml plasma sample from a normal man was studied. His plasma concentration of luteinizing hormone was 11.8 IU per liter; of follicle-stimulating hormone, 9.0 IU per liter; and of testosterone, 18.9 nmol per liter. Blood from all the subjects was drawn between 8 a.m. and noon into tubes treated with heparin. The plasma was separated, and a portion of the sample was saved for the cynomolgus bioassay. Plasma testosterone,9 luteinizing hormone,10 and follicle-stimulating hormone 11 were measured in the remainder. All the children were enrolled in studies approved by the institutional review board of the National Institute of Child Health and Human Development (NICHHD). Informed consent was provided by a parent, and assent for studies was obtained from the older children.

GnRH Antagonist

A short-acting GnRH antagonist was given to the monkeys to suppress their endogenous secretion of luteinizing hormone and thus increase the likelihood of detecting exogenous luteinizing-hormone–like activity. The antagonist, [achéal-n-Nal1-D-Cl(4)-Phe2-D-Trp3-D-Arg6-D-Ala10]—luteinizing-hormone-releasing hormone, was synthesized at the Salk Institute and made available by the Contraceptive Development Branch, Center for Population Research, NICHHD. It was reconstituted in sterile water at a concentration of 12 mg per milliliter and kept frozen until injection.

Monkeys and Bioassay Procedure

The use of the monkeys for this study was approved by the animal-use review board of the NICHHD. Adult male cynomolgus monkeys with a mean weight of 6.1 kg (range, 4.7 to 7.4) were used. Each monkey received a 6-mg (0.5-ml) subcutaneous injection of the GnRH antagonist at 4 p.m. on the day before the study. This dose was approximately twice that used by Adams et al.12 to suppress gonadotropin secretion for at least 24 hours in adult male cynomolgus monkeys. The animals were anesthetized with ketamine (10 mg per milliliter) and xylazine (Rompun; 20 mg per milliliter) in a ratio of 3:7. The initial dose was 0.1 ml per kilogram of body weight. Additional smaller doses were given as needed to maintain anesthesia. Lidocaine (Xylocaine; 1 percent) was infiltrated at both sides of catheter placement. The femoral artery was exposed, and sutures were placed to control bleeding. A sterile catheter (internal diameter, 0.064 cm) was placed in the femoral artery and was advanced under fluoroscopic guidance into the left testicular artery through the aorta. A single radiograph was taken after the injection of 0.5 ml of a radiopaque contrast agent to document the placement of the catheter. Once in place, the catheter was pulled back slightly until the time of the infusion. The catheter was flushed periodically with heparin-treated saline to maintain its patency. The internal jugular vein was then exposed. Ligatures were placed to control bleeding. A second catheter was placed in the internal jugular vein and threaded under fluoroscopic guidance to the left testicular vein through the inferior vena cava and left renal vein. The placement of the catheter was checked by the retrograde injection of contrast agent into the left testicular vein. An infusion of normal saline (50 ml per hour) was started in the venous line to maintain patency and hydration. All procedures were performed with use of an aseptic technique.

Base-line blood samples were drawn from the testicular venous catheter 30 minutes, 15 minutes, and immediately before the injection of test plasma. Immediately after the final base-line sample was obtained, the arterial catheter was advanced in the left testicular artery, and plasma (3 ml) from a patient with familial male precocious puberty or a normal boy (selected randomly in a blinded fashion) was slowly infused at a rate of 1 ml per minute. A small amount of contrast agent was injected after the infusion of plasma to ensure that the catheter was in the testicular artery. The arterial catheter was then withdrawn into the aorta for the remainder of the study. After the infusion of plasma, samples of testicular venous blood were drawn every 15 minutes for periods ranging from 180 to 300 minutes to measure plasma testosterone. Blood samples were also taken from the testicular artery 15 minutes and immediately before infusion and 15, 45, 75, 105, 135, and 165 minutes after infusion to measure monkey luteinizing hormone. The blood samples were kept on ice during the procedure and were centrifuged at 4°C immediately after each study had been completed. The plasma was frozen at — 20°C until assay. When the venous sampling was completed, both catheters were removed from the monkey, the vein and artery were tied, and the operative wounds were sutured.

Because several monkeys had peak plasma testosterone levels at the end of the three-hour sampling period used in the initial studies, we studied the responses to plasma from three patients with familial male precocious puberty and three normal subjects for a five-hour period. The monkeys used in these longer studies received an additional 6 mg of GnRH antagonist at 8 a.m. on the day of the study because the study lasted for more than 24 hours after the first dose of antagonist.

All the monkeys studied for five hours and all but one of the monkeys studied for three hours were used only once, because stenosis of the testicular vein developed, making recatheterization impossible. One animal received plasma from a patient and from a normal subject on separate occasions four months apart.

Hormone Assays

Testosterone was measured in each sample of testicular venous plasma by radioimmunoassay.9 The interassay coefficient of variation was 12.1 percent, and the intraassay coefficient of variation was 6.2 percent. There was less than 0.01 percent cross-reactivity of testolactone in the testosterone assay. Luteinizing hormone was assayed by the method of Niswender et al.13 in the samples of testicular arterial plasma obtained during the three-hour study; the assay had a sensitivity of 20 to 30 μg per liter. The standard used was rhesus reference preparation 1 (RP-1). The interassay coefficient of variation was 7.5 percent, and the intraassay coefficient of variation was 2.2 percent. The bioactivity of luteinizing hormone was measured by the method of Dufau et al.14 in all samples of venous plasma obtained during the five-hour studies. The sensitivity of this assay was 4.25 μg per liter of rhesus RP-1. Plasma concentrations of luteinizing hormone and follicle-stimulating hormone were measured in the patients and normal subjects by radioimmunoassay as previously described.10 , 11 All measurements were carried out at Hazleton Biotechnologies (Vienna, Va.). All samples from an individual study were analyzed in duplicate in a single assay.

Statistical Analysis

Statistical comparisons between the responses (the peak levels of testosterone in testicular venous plasma as a percentage of the baseline levels, defined as the means of the values 30 minutes, 15 minutes, and immediately before the infusion of plasma from the patients and from the control subjects) and the areas under the curve (calculated as the percentage increase relative to base line, with use of the trapezoidal rule) were made with Student's two-tailed t-test. Clinical data from the patients and the normal boys were also compared with Student's two-tailed t-test.

Results

Plasma Levels of Luteinizing Hormone in the Monkeys

The plasma levels of luteinizing hormone were undetectable or near the limit of detection of the assay during the three-hour studies (<20 to 30 μg per liter) in the animals that received plasma from the patients and in those that received plasma from the normal subjects. The bioactivity of luteinizing hormone in the samples collected during the five-hour studies was undetectable (<4.25 μg per liter of rhesus RP-1). The plasma levels of bioactive luteinizing hormone in normal adult cynomolgus monkeys were 5 to 50 μg per liter of rhesus RP-1.

Plasma Testosterone Response in the Monkeys

Figure 1. Figure 1. Plasma Testosterone Responses in Three Monkeys after the Infusion of Plasma from a Normal Man (○), a Boy with Familial Male Precocious Puberty (•), and a Normal Prepubertal Boy (□).

The peak plasma testosterone concentrations in response to infusion of plasma from a normal adult man, a boy with familial male precocious puberty, and a normal prepubertal boy are shown in Figure 1. The peak response to the plasma from the adult was 911 percent. The testis-stimulating activity of the plasma from the boy with familial male precocious puberty was intermediate between that of the prepubertal boy and that of the man.

Figure 2. Figure 2. Peak Plasma Testosterone Responses in Monkeys Studied for Three Hours after the Infusion of Plasma from 12 Boys with Familial Male Precocious Puberty (FMPP) or Plasma from 7 Normal Boys and 1 Boy with Hypogonadotropic Hypogonadism Receiving Testosterone Therapy (Control) (Left Panel) and in the Monkeys Studied for Five Hours after the Infusion of Plasma from 3 Boys with FMPP or Plasma from 3 Normal Boys (Right Panel). The solid circles with attached vertical bars indicate mean ±SE values.

The mean (±SE) peak testosterone response, expressed as a percentage of the mean level at base line, was greater in the monkeys that received plasma from the 12 boys with familial male precocious puberty than in the monkeys that received plasma from the 7 normal boys and 1 boy with hypogonadotropic hypogonadism (385±51 vs. 184±25 percent, P<0.005) (Fig. 2). The peak response to plasma from the boy with hypogonadotropic hypogonadism who was receiving parenteral testosterone therapy and who had a plasma testosterone level similar to that in the boys with familial male precocious puberty was 150 percent — similar to the responses of the normal boys. The lowest response to plasma from a boy with familial male precocious puberty was 95 percent, and the highest response to plasma from a normal boy was 349 percent. Only one monkey had a peak value of less than 195 percent in response to an infusion of plasma from a boy with familial male precocious puberty, and only one monkey had a peak value of more than 195 percent in response to plasma from a normal boy. The mean (±SE) areas under the testosterone-response curves were not significantly different in the monkeys that received plasma from the boys with precocious puberty (91 ±30 percent of base line) and those that received plasma from the normal boys (20±41 percent of base line, P>0.05). In the one monkey that received plasma on two occasions, there was a much greater response to the infusion of plasma from the boy with familial male precocious puberty (base-line testosterone value, 57 nmol per liter; peak, 336 nmol per liter) than to the infusion of plasma from the normal boy (base-line, 54 nmol per liter; peak, 77 nmol per liter).

The mean (±SD) time of the peak testosterone response during the three-hour study in the monkeys that received plasma from the boys with familial male precocious puberty was 148±52 minutes (range, 30 to 180). Nine of the 12 peak levels occurred between 150 and 180 minutes after infusion. The peak responses to the infusions of plasma from the two brothers studied occurred after 180 minutes, and the increases in testosterone were similar (258 and 308 percent of the mean base-line level). The peak testosterone levels in monkeys that received plasma from the normal boys also occurred after 150 to 180 minutes in all but one study, in which the peak occurred after 75 minutes.

Figure 3. Figure 3. Plasma Testosterone Response in Monkeys Studied for 300 Minutes after the Infusion of Plasma from Three Normal Prepubertal Boys (Open Symbols) and Three Boys with Familial Male Precocious Puberty (Solid Symbols).

Several of the monkeys that received plasma from either a normal boy or a boy with familial male precocious puberty had peak plasma testosterone concentrations after 180 minutes. We therefore extended the sampling period to 300 minutes in six monkeys (three that received plasma from boys with familial male precocious puberty and three that received plasma from normal boys) (Fig. 3). The mean (±SE) peak plasma testosterone response relative to base line (363±81 vs. 115±6 percent) was significantly greater (P<0.01) after the infusion of plasma from the boys with familial male precocious puberty than after the infusion of plasma from normal boys (Fig. 2), and there was no delayed rise in testosterone in the monkeys that received plasma from the normal boys. The area under the response curve (the percentage increase relative to base line) was also significantly larger in the monkeys that received plasma from the boys with familial male precocious puberty than in those that received plasma from the normal boys (154±34 vs. —58±10 percent, P<0.005).

Discussion

The hypothesis that there is a circulating factor other than luteinizing hormone and follicle-stimulating hormone that stimulates the secretion of testosterone in boys with familial male precocious puberty is not new.2 , 4 Holland et al., using a mouse Leydig-cell bioassay and a rat ovarian-membrane radioreceptor assay to measure plasma levels of bioactive luteinizing hormone, recently presented preliminary evidence that patients with familial male precocious puberty have an increased ratio of bioactive to immunoreactive luteinizing hormone in plasma.5 Several previous investigators, however, failed to detect any difference in levels of bioactive luteinizing hormone between boys with familial male precocious puberty and normal boys1 , 4 (and Kenigsberg D, Hsueh A, and Ewing L: personal communications). Rosenthal et al.2 attempted without success to identify an immunoglobulin with luteinizing-hormone–like activity in the serum of their patients by direct immunofluorescence. These results tended to support the hypothesis that a genetic error in the intratesticular regulation of testosterone biosynthesis leads to autonomous gonadal function in such children. An alternative explanation, however, is that the disorder is due to a circulating factor active only in humans and some but not all other species.

Our results demonstrate qualitatively that boys with familial male precocious puberty have a factor in plasma that can stimulate monkey testes to secrete testosterone. Why this factor is inactive in the rodent system is not known. Perhaps it can be explained by species specificity or by the requirement of an intact Leydig—Sertoli paracrine relation for the expression of activity. Sertoli's cells function in many patients with familial male precocious puberty, since developing spermatozoa have been identified in testicular-biopsy specimens of some boys with the disorder and since affected men are fertile.1 , 2 , 4 The relation between Leydig and Sertoli's cells is preserved in the bioassay we used, and the species we studied is closer to humans on the phylogenetic tree. To our knowledge, no other convincing evidence for a testis-stimulating factor in familial male precocious puberty has been published.

The plasma from 11 of 12 boys with familial male precocious puberty stimulated an increase in plasma testosterone in monkeys that was larger than the largest response in a monkey given plasma from all but 1 of the normal boys. The times of the peak responses in the two groups were similar. The plasma from the normal man caused a larger rise in monkey plasma testosterone than did plasma from any of the patients, but the time courses of the responses were similar.

The infusions of plasma from normal boys were associated with an 84 percent increase in plasma testosterone levels in the cynomolgus bioassay. This increase was approximately twice as large as could have been expected on the basis of random fluctuations in plasma testosterone during the three-hour sampling period, given the mean (±SE) coefficient of variation of testosterone levels at base line (13.2±1.6 percent). Possible explanations for this increase include the partial escape of monkey luteinizing-hormone secretion from the suppressive effect of the GnRH antagonist, the sensitivity of the bioassay to the small amount of luteinizing hormone present in the plasma of prepubertal boys, and a nonspecific response to human plasma. To address the issue of partial escape from the GnRH antagonist, we gave a second dose of antagonist immediately before the five-hour studies. With this protocol, plasma levels of bioactive luteinizing hormone in the monkeys were undetectable throughout the experiment, and the infusion of plasma from normal boys caused a mean testosterone increase of only 15±6 percent, as compared with 263±81 percent for the plasma from boys with familial male precocious puberty (P<0.01). The data are thus consistent with the hypothesis that the small responses to the infusions of plasma from normal boys were due to the fact that the secretion of luteinizing hormone in the monkeys partially escaped inhibition because of the single dose of GnRH antagonist.

We conclude that patients with familial male precocious puberty have a circulating testis-stimulating factor. The production of such a factor would explain the biologic nature of the disorder.

Funding and Disclosures

We are indebted to Dr. Louisa Laue for providing patients for this study, to Janet Jones, R.N., for providing nursing care, to Dr. Andres Negro-Vilar for his support, and to Ms. Kathy Shoobridge and Ms. Loretta Moore for assistance in the preparation of the manuscript.

Author Affiliations

From the Developmental Endocrinology Branch, National Institute of Child Health and Human Development (P.K.M., P.P.F., K.M.B., G.B.C., D.L.L., B.D.A.), and the Department of Radiology, Clinical Center (M.E.G., R.L.D.), National Institutes of Health, Bethesda, Md., and the Department of Radiology, Georgetown University Hospital, Washington, D.C. (J.L.D.). Address reprint requests to Dr. Cutler at the Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bldg. 10, Rm. 10N262, Bethesda, MD 20892.

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Citing Articles (18)

    Figures/Media

    1. Table 1. Clinical Features and Plasma Hormone Values in 12 Boys with Familial Male Precocious Puberty and 7 Normal Boys.*
      Table 1. Clinical Features and Plasma Hormone Values in 12 Boys with Familial Male Precocious Puberty and 7 Normal Boys.*
    2. Figure 1. Plasma Testosterone Responses in Three Monkeys after the Infusion of Plasma from a Normal Man (○), a Boy with Familial Male Precocious Puberty (•), and a Normal Prepubertal Boy (□).
      Figure 1. Plasma Testosterone Responses in Three Monkeys after the Infusion of Plasma from a Normal Man (○), a Boy with Familial Male Precocious Puberty (•), and a Normal Prepubertal Boy (□).
    3. Figure 2. Peak Plasma Testosterone Responses in Monkeys Studied for Three Hours after the Infusion of Plasma from 12 Boys with Familial Male Precocious Puberty (FMPP) or Plasma from 7 Normal Boys and 1 Boy with Hypogonadotropic Hypogonadism Receiving Testosterone Therapy (Control) (Left Panel) and in the Monkeys Studied for Five Hours after the Infusion of Plasma from 3 Boys with FMPP or Plasma from 3 Normal Boys (Right Panel). The solid circles with attached vertical bars indicate mean ±SE values.
      Figure 2. Peak Plasma Testosterone Responses in Monkeys Studied for Three Hours after the Infusion of Plasma from 12 Boys with Familial Male Precocious Puberty (FMPP) or Plasma from 7 Normal Boys and 1 Boy with Hypogonadotropic Hypogonadism Receiving Testosterone Therapy (Control) (Left Panel) and in the Monkeys Studied for Five Hours after the Infusion of Plasma from 3 Boys with FMPP or Plasma from 3 Normal Boys (Right Panel). The solid circles with attached vertical bars indicate mean ±SE values.
    4. Figure 3. Plasma Testosterone Response in Monkeys Studied for 300 Minutes after the Infusion of Plasma from Three Normal Prepubertal Boys (Open Symbols) and Three Boys with Familial Male Precocious Puberty (Solid Symbols).
      Figure 3. Plasma Testosterone Response in Monkeys Studied for 300 Minutes after the Infusion of Plasma from Three Normal Prepubertal Boys (Open Symbols) and Three Boys with Familial Male Precocious Puberty (Solid Symbols).

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