Pituitary-gonadal axis in male undermasculinisation.

AIMS: To study the value of assessing serum concentrations of luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone, and dihydrotestosterone (DHT) in patients with male undermasculinisation not caused by androgen insensitivity. METHODS: A retrospective study of a register of cases of male undermasculinisation (20 with abnormal testes, eight with 5alpha-reductase deficiency, three with testosterone biosynthetic defects, seven with Drash syndrome, and 210 undiagnosed). RESULTS: A human chorionic gonadotropin (hCG) stimulation test was performed in 66 of 185 children with male undermasculinisation. In 41 of 66 patients the dose of hCG was either 1000 U or 1500 U on three consecutive days. The rise in testosterone was related to basal serum testosterone and was not significantly different between the two groups. Testosterone:DHT ratio in patients with 5alpha-reductase deficiency was 12.5-72.8. During early infancy, baseline concentrations of LH and FSH were often within normal reference ranges. In patients with abnormal testes, median pre-LHRH (luteinising hormone releasing hormone) concentrations of LH and FSH were 2 and 6.4 U/l, respectively, and post-LHRH concentrations were 21 and 28 U/l. An exaggerated response to LHRH stimulation was observed during mid-childhood in children where the diagnosis was not clear and in all children with abnormal testes. CONCLUSIONS: The testosterone:DHT ratio following hCG stimulation is more reliable than the basal testosterone:DHT ratio in identifying 5alpha-reductase deficiency. During infancy, the LHRH stimulation test may be more reliable in identifying cases of male undermasculinisation due to abnormal testes than basal gonadotrophin concentrations.     

Assessment of the gonadotrophin-gonadal axis in androgen insensitivity syndrome.

OBJECTIVE: To study the value of measuring serum luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone, and dihydrotestosterone (DHT) in androgen insensitivity syndrome (AIS). DESIGN: Retrospective study of patients on a nationwide register of AIS. PATIENTS: Sixty one cases of AIS with androgen receptor (AR) dysfunction (abnormalities of the AR gene and/or abnormal AR binding) were divided into three age groups: infants, < 1 year old; children, 1-13 years old; and postpubertal, > 13 years old. MEASUREMENTS: Age, dose of human chorionic gonadotrophin (hCG) stimulation, pre-hCG and post-hCG serum testosterone values, serum DHT values, and serum LH and FSH values before and after LH releasing hormone (LHRH) stimulation. RESULTS: In 23 of 30 infants testosterone was within age related reference ranges; six were above this range. The median testosterone rise following variable dosage of hCG was 9.5 times the basal value. The increment was not related to the hCG dose, age, or basal concentration of testosterone. The median basal and stimulated testosterone:DHT ratios were 2.5 and 6.1, respectively. The median increment in DHT was 2.2-fold. Seventeen of 18 FSH and 11 of 19 LH measurements were within age related ranges in infants; in seven patients LH values were above the range. LHRH stimulation performed in 39 patients showed an exaggerated LH in all age groups. The FSH response was not exaggerated in children. CONCLUSION: Although a positive hCG test excludes biosynthetic defects of testosterone, an inadequate response does not exclude AIS. Basal LH and testosterone may not be raised during early infancy. An LHRH stimulation test might be useful for evaluating cases of suspected AIS presenting in mid-childhood.     

Hypothalamo-Hypophyseal-Testicular Function in Prepubertal Boys with Acute Lymphoblastic Leukemia following Chemotherapy and Testicular Radiotherapy

ABSTRACT. Hypothalamo-hypophyseal-testicular function was studied in twenty-eight prepubertal boys with ALL in clinical and haematological remission. Eighteen were treated with combined systemic chemotherapy (24–36 months) and the other ten, who had testicular leukemic infiltrates, received chemotherapy (38–60 months) and testicular radiotherapy (2000 rad). Plasma levels of LH and FSH were measured before and after stimulation with LHRH (100 μg i.v.) and plasma levels of testosterone before and after stimulation with hCG (1500 IU/48 h/7 doses). In patients treated with chemotherapy alone, mean basal LH and FSH, mean responses to LHRH stimulation and mean testosterone levels after stimulation with hCG did not significantly differ from those of the controls. Five of these patients who had normal testosterone values after three doses of hCG had testosterone values below the normal range after seven doses. In patients treated with chemotherapy and testicular radiotherapy, mean basal FSH and mean responses to LHRH stimulation were significantly higher than those of the controls. Testosterone values after stimulation with hCG were low in three and very low in the other seven. In both groups of patients data from testicular biopsies were consistent with functional results. We conclude that chemotherapy causes slight testicular damage, but chemotherapy and testicular radiotherapy produce severe testicular damage in patients with testicular leukemic infiltrates.     

Ovarian function after bone marrow transplantation performed before menarche

AIM—To examine the long term effect of bone marrow transplantation (BMT) on ovarian function in girls.
METHODS—Eighteen girls who underwent BMT before menarche, had been disease free for more than six years, and were over 14 years of age at the time of study were investigated. The preparative regimen consisted of irradiation and chemotherapy. The occurrence of menarche and changes in basal serum follicle stimulating hormone (FSH) concentrations were studied.
RESULTS—Twelve patients achieved menarche at a median age of 12.8 years. Age at transplant was significantly younger in patients who achieved menarche than in those who did not (mean (SD), 7.2 (0.5) v 11.1 (1.7) years). Basal FSH began to rise to menopausal concentrations after 10 years of age, and the girls who did not experience menarche had a sustained rise in FSH concentrations. Among those with raised FSH concentrations, five girls experienced menarche while serum FSH values were decreasing and four achieved menarche while FSH remained raised.
CONCLUSIONS—The high incidence of menarche suggests a favourable outcome of ovarian function in girls who undergo BMT at a young age.

     

Hypothalamo-hypophyseal-testicular function in prepubertal boys with acute lymphoblastic leukemia following chemotherapy and testicular radiotherapy

Hypothalamo-hypophyseal-testicular function was studied in twenty-eight prepubertal boys with ALL in clinical and haematological remission. Eighteen were treated with combined systemic chemotherapy (24-36 months) and the other ten, who had testicular leukemic infiltrates, received chemotherapy (38-60 months) and testicular radiotherapy (2 000 rad). Plasma levels of LH and FSH were measured before and after stimulation with LHRH (100 micrograms i.v.) and plasma levels of testosterone before and after stimulation with hCG (1 500 IU/48 h/7 doses). In patients treated with chemotherapy alone, mean basal LH and FSH, mean responses to LHRH stimulation and mean testosterone levels after stimulation with hCG did not significantly differ from those of the controls. Five of these patients who had normal testosterone values after three doses of hCG had testosterone values below the normal range after seven doses. In patients treated with chemotherapy and testicular radiotherapy, mean basal FSH and mean responses to LHRH stimulation were significantly higher than those of the controls. Testosterone values after stimulation with hCG were low in three and very low in the other seven. In both groups of patients data from testicular biopsies were consistent with functional results. We conclude that chemotherapy causes slight testicular damage, but chemotherapy and testicular radiotherapy produce severe testicular damage in patients with testicular leukemic infiltrates.     

The effect of testicular irradiation on Leydig cell function in prepubertal boys with acute lymphoblastic leukaemia.

Testicular function was investigated by the luteinising hormone releasing hormone (LHRH) test and a three day human chorionic gonadotrophin (HCG) test in 11 prepubertal boys with acute lymphoblastic leukaemia (ALL) who had received 2400 rads of fractionated radiation to their testes after relapse at this site. The results were compared with an unirradiated control group. Basal and peak testosterone values after 1000 units of HCG were significantly lower in the irradiated patients than in the control group. Peak follicle stimulating hormone (FSH) values after 100 micrograms LHRH were significantly higher in irradiated boys, but there was no difference in either basal FSH or basal and peak luteinising hormone values. The findings suggest that the ability of the Leydig cell to produce testosterone--as detected by the HCG test--is appreciably reduced after irradiation and that tubular dysfunction in prepubertal boys may sometimes be predicted by a raised FSH response.     

Hypergonadotropic Hypogonadism in Newborn Males with Primary Testicular Failure

ABSTRACT. Four infants with genital ambiguity but with apparent testes were given a gonadotropin-releasing hormone (GnRH) test and a human chorionic gonadotropin (hCG) test at age 3–12 days. The results were compared with those from 16 newborn males (aged 2 to 6 days) with minor genital anomalies; 9 with unilateral and 3 with bilateral incomplete testicular descent, 2 with surgically insignificant glandular hypospadias and 2 with penis length <(-2 SD) for gestational age. Treatment with testosterone resulted in clear phallus growth in all four patients. All four patients had elevated basal luteinizing hormone (LH) concentrations as well as an exaggerated LH response to GnRH; three of them also had an exaggerated follicle stimulating hormone (FSH) response. Thus in all patients the etiology of genital ambiguity was considered to be testicular. The testosterone response to hCG was normal in two of the patients but impaired in the other two. The steroidogenic response did not show any specific enzyme defect. We conclude that 1) newborn boys with Leydig cell failure are clearly hypergonadotropic, 2) the GnRH test is a more sensitive indicator of Leydig cell failure neonatally than the hCG test and 3) normal testes greatly inhibit the secretion of both LH and FSH during the first week of life.     

Endocrine studies in Blackfan-diamond anemia: Evidence for hypothalamic-pituitary dysfunction under frequent transfusion therapy

A 13 year old boy with Blackfan-Diamond anemia treated with frequent transfusions was investigated for endocrine abnormalities. Prepubertal plasma LH and FSH values, lack of sleep-related hormone rhythms of the gonadotropins, as well as prepubertal responses of LH and FSH to acute stimulation with LHRH strongly suggests that a hypothalamic-pituitary abnormality is the cause of the hypogonadotropic hypogonadism observed in this patient. As a result of impaired stimulation of the gonads plasma testosterone was prepubertal. A three-to fourfold increase of basal plasma PRL values was found without any signs of a typical sleep-dependent increase. Values obtained ranged between 21 ng/ml and 24 ng/ml (normal range 5–8 ng/ml). A normal response to TRH stimulation was found.These results suggest that hemosiderosis may responsible for the hyperprolactinemia as a result of hypothalamic-pituitary dysfunction. Furthermore, dysfunction is demonstrated by prepubertal responses of LH and FSH to LHRH stimulation.Abbreviations LH luteinizing hormone - FSH follicle-stimulating hormone - PRL prolactin - LHRH luteinizing-hormone-releasing hormone - TRH thyrotropin releasing hormone - PIF prolactin inhibiting factor     

Smith-Lemli-Opitz syndrome: in vivo and in vitro study of testicular function in a prepubertal patient with ambiguous genitalia

The pathogenesis of the development of ambiguous genitalia reported in some 46,XY patients with Smith-Lemli-Opitz syndrome is not understood. Presumably, it is related to the 7-dehydrocholesterol reductase deficiency present in these patients. In this study we have evaluated testicular function, both in vivo and in vitro, in a 46,XY patient with ambiguous genitalia, reared as a girl. The diagnosis was based on clinical features, low serum cholesterol and high serum 7-dehydrocholesterol levels. Serum hormone values, determined during the first month of age, showed normal basal testosterone (1.95 ng/ml), LH (0.91 U/l) and FSH (2.51 U/l). However, serum testosterone did not increase after hCG administration (1.98 ng/ml). On the other hand, the patient had a positive biological response to exogenous testosterone (decrease in sex hormone-binding globulin serum levels). She was orchidectomized at the age of 33 mo. Testicular cells were dispersed and maintained in culture for 6 d. These cells showed a very good capacity to secrete testosterone into the culture medium (X +/- SD, 26.1 +/- 11.7 vs. 4.36 +/- 1.70 pmol/10(6) cells/24 h in a control group of testicular cells prepared from testes collected at necropsy). The patient's cells failed to respond to LH stimulation (18.6 +/- 4.0 pmol/10(6) cells/24 h), although they did respond to other stimuli. It is concluded that the severe cholesterol deficiency of this patient did not impair the capacity of the testes to synthesize testosterone. However, the LH/hCG receptor or its subsequent message was activated neither in vivo nor in vitro. This finding suggests that the foetal testes might have failed to respond to placental hCG at the time of male external genital differentiation. This failure could have been responsible for the ambiguous genitalia present in this patient.     

Treatment of hypogonadal adolescent boys with long acting subcutaneous testosterone pellets

Accepted 26 February
AIMS—Long acting subcutaneous testosterone pellets are of proved efficacy for the treatment of hypogonadal men, but have not been reported as a treatment modality in adolescent boys. Pharmacodynamic studies of subcutaneous testosterone release have shown prolonged normalisation of testosterone levels for at least four months. Administration of a long acting, safe, effective, and convenient form of treatment is desirable when life- long treatment is indicated.
PATIENTS AND METHODS—Eighteen boys (aged 13.9-17.5 years at the start of treatment)—seven with primary hypogonadism, nine with secondary hypogonadism, and two boys being treated with testosterone for tall stature—were given testosterone pellets (8-10 mg/kg) every six months for 18months. Height, weight, pubertal status, and psychosocial parameters were assessed and follicle stimulating hormone, luteinising hormone, testosterone, prolactin, and lipids were measured at 0, 1, 3,6, 12, and 18 months. Bone age was measured at 0 and 12months.
RESULTS—In all boys growth velocity continued appropriately for bone age. Puberty continued to progress in all boys and in two boys the amount of virilisation exceeded that seen with previous treatment with intramuscular testosterone. After testosterone administration, follicle stimulating hormone and luteinising hormone suppressed incompletely in the boys with primary hypogonadism. Serum testosterone ranged from 4.3 to 26.7 nmol/l at three months to less than 10nmol/l at six months after implantation. Prolactin and lipid levels were normal throughout the study. By report, there was an improvement in mood and emotional wellbeing. No pellet extrusions occurred in a total of 156 pellet insertions.
CONCLUSIONS—All boys preferred this mode of testosterone administration to intramuscular injections. Long acting subcutaneous testosterone pellets are safe, efficacious, well tolerated, and convenient, and result in normal physical growth and improved psychological outlook in adolescent hypogonadal boys.

• Continued normal progress of growth and pubertal status occurs with subcutaneous testosterone • Prolonged stable physiological levels of testosterone are maintained for four to six months • Bone age advance is commensurate with change in chronological age • Psychological outlook and self image are reported to be improved • Subcutaneous testosterone is safe, well tolerated, efficacious, and convenient     

Hypergonadotropic hypogonadism in newborn males with primary testicular failure

Four infants with genital ambiguity but with apparent testes were given a gonadotropin-releasing hormone (GnRH) test and a human chorionic gonadotropin (hCG) test at age 3-12 days. The results were compared with those from 16 newborn males (aged 2 to 6 days) with minor genital anomalies; 9 with unilateral and 3 with bilateral incomplete testicular descent, 2 with surgically insignificant glandular hypospadias and 2 with penis length less than (means-2 SD) for gestational age. Treatment with testosterone resulted in clear phallus growth in all four patients. All four patients had elevated basal luteinizing hormone (LH) concentrations as well as an exaggerated LH response to GnRH; three of them also had an exaggerated follicle stimulating hormone (FSH) response. Thus in all patients the etiology of genital ambiguity was considered to be testicular. The testosterone response to hCG was normal in two of the patients but impaired in the other two. The steroidogenic response did not show any specific enzyme defect. We conclude that newborn boys with Leydig cell failure are clearly hypergonadotropic, the GnRH test is a more sensitive indicator of Leydig cell failure neonatally than the hCG test and normal testes greatly inhibit the secretion of both LH and FSH during the first week of life.     

Gonadotrophin response to LH-RH in boys with delayed growth and adolescence.

Plasma luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations were measured before and after intravenous luteinising hormone-releasing hormone (LH-RH) in 33 boys with growth delay. Eighteen were prepubertal and 15 pubertal. Basal LH and FSH levels were low in both groups with mean increments after LH-RH of 3.2 +/- 0.8 U/l (mean +/- SEM) and 2.6 +/- 0.4 U/l respectively in the prepubertal and 7.4 +/- 0.7 U/l and 2.0 +/- 0.3 U/l in the pubertal boys. The LH increment showed a positive correlation with increasing bone age (r = 0.71, P less than 0.001); FSH did not. The LH-RH response thus appeared normal in relation to the stage of maturity.     

Molecular genetic analysis and human chorionic gonadotropin stimulation tests in the diagnosis of prepubertal patients with partial 5α-reductase deficiency

Reduced conversion of testosterone (T) to dihydrotestosterone (DHT) results in defective virilization in karyotypic males. Different mutations in the 5-reductase type 2 gene cause the phenotypic variability of the disease. In this report we describe four prepubertal patients with a predominantly male phenotype who carry homozygous point mutations in the 5-reductase type 2 gene and address the specific T and DHT response to different human chorionic gonadotropin (hCG) stimulation tests. For molecular genetic analysis, DNA from peripheral blood leucocytes was studied. The coding region of the 5-reductase type 2 gene was characterized by exon-specific polymerase chain reaction amplification, non-radioactive single strand polymorphism analysis, and direct sequencing. Three different homozygous point mutations (Gly₁₉₆–Ser, Arg₂₂₇–Gln and Ala₂₂₈–Thr) were identified in the patients. In contrast, in the DNA from 100 phenotypically normal males only two heterozygous abnormalities (Ile₁₉₆–Ile, Met₁₅₇) were characterized. For hormonal studies, T and DHT were measured in serum before and after hCG stimulation employing different protocols. HCG stimulation with 5000 IU/m² once and prolonged stimulation with seven injections of 1500 IU hCG per single dose every other day were used.Conclusion While abnormal T/DHT ratios were identified with both hCG protocols in the patients, prolonged stimulation lead to higher T values and to higher T/DHT ratios, and hence to a better discrimination of pathologic results.     

Final height of short subjects of low birth weight with and without growth hormone treatment

AIM—To compare final height in two groups of low birth weight children examined for short stature: the first group untreated because of normal growth hormone (GH) secretion, the second treated with human growth hormone (hGH) because of abnormal secretion.
METHODS—A total of 49 subjects born at term of birth weight below the 10th centile were consecutively examined for idiopathic short stature. The first group of subjects (n = 20) with normal GH peaks after pharmacological tests (>8 µg/l) spontaneously reached final height. The second group (n = 29) with abnormal secretion were treated with hGH (20 U/m²/week) for 36-84 months. At diagnosis the two groups were of similar height for chronological age and bone age, and had similar target height.
RESULTS—In both groups final height was significantly lower than target height (−0.65 (SEM 0.20) in untreated cases, −0.61 (0.18) in treated cases). Fewer than one third of subjects had a final height above target height. Final height data of untreated and treated cases were not different. In the treated group the best results were obtained by those subjects who improved their height for bone age after three years of therapy.
CONCLUSIONS—Our subjects with birth weight below the 10th centile remained as short adults with final height below target height. Treatment with hGH 20 U/m²/week in those diagnosed as deficient was not effective, with final results overlapping those of untreated subjects.

     

Accelerated pubertal development in patients with shunted hydrocephalus

OBJECTIVE: To evaluate pubertal development and peripheral concentrations of gonadotrophins and sex hormones in children with shunted hydrocephalus compared with healthy controls. STUDY DESIGN: 114 patients (52 females, 62 males) and 73 healthy controls (35 females, 38 males) aged 5 to 20 years were analysed for stage of puberty, age at menarche, testicular volume, basal serum follicle stimulating hormone (FSH), luteinising hormone (LH), sex hormone binding globulin (SHBG), testosterone and oestradiol concentrations, and free androgen index. RESULTS: Male gonadal and male and female pubic hair development occurred significantly earlier in the patients than in the controls. The mean age at menarche was significantly lower in the female patients than in their controls (11.7 v 13.2 years; p < 0.001), and lower than it had been for their mothers (v 13.1 years; p < 0.001). Relative testicular volume was higher in the male patients than in their controls (1.2 standard deviation score (SDS) v 0.2 SDS; p < 0.001). The prepubertal patients had higher basal LH (0.13 U/l v 0.08 U/l; p < 0.001) and SHBG (132.3 nmol/l v 109.1 nmol/l; p < 0.01) than the controls. Both the prepubertal and pubertal females had significantly higher basal FSH than their controls (1.57 U/l v 1.03 U/l; p < 0.05, and 4.0 U/l v 2.9 U/l; p < 0.01, respectively). CONCLUSIONS: Hydrocephalic children experience accelerated pubertal maturation, reflected in a younger age at menarche in females and an increased testicular volume in males. This may be because of enhanced gonadotrophin secretion, possibly resulting from unphysiological variations in intracranial pressure.     

Testicular function after combination chemotherapy in childhood for acute lymphoblastic leukaemia.

We have assessed testicular function with luteinising hormone-releasing hormone (LH-RH) and human chorionic gonadotrophin stimulation tests in 44 boys previously treated with, or currently receiving, chemotherapy for acute lymphoblastic leukaemia (ALL). At the same time a testicular biopsy was performed in each boy and the morphology was studied. Histologically the chemotherapy appeared to damage the tubular system in particular, and the degree of damage was assessed by estimating the tubular fertility (TF) index which is defined as the percentage of seminiferous tubules containing identifiable spermatogonia. The mean TF index in all 44 biopsies was 51%. Only 2 of the 44 boys showed an absent or blunted testosterone response to human chorionic gonadotrophin. This suggests that Leydig cell function is rarely impaired by such chemotherapy and that most of the boys, similarly treat for ALL, will undergo normal pubertal maturation. Apart from the basal luteinising hormone (LH) levels in the prepubertal group which could not be compared, the median basal serum follicle-stimulating hormone (FSH), LH, and testosterone concentrations, the median peak FSH and LH responses to LH-RH, and the mean plasma testosterone responses to human chorionic gonadotrophin stimulation did not differ between the prepubertal, early pubertal, and late pubertal groups compared with normal boys of similar pubertal maturation. Three of 32 prepubertal ALL boys, and 5 of 12 pubertal ALL boys showed abnormalities of gonadotrophin secretion. The increased frequency of abnormalities of FSH secretion in the pubertal ALL boys compared with the prepubertal ALL boys could not be explained by more severe tubular damage in the former group. We conclude that moderately severe damage to the tubular system of the testis unassociated with Leydig cell impairment may not be detected in the prepubertal boy with current tests of testicular function.     

Hormonal profile of puberty in South Australian children I

Serum follicle stimulating hormone (FSH), luteinising hormone (LH) and testosterone (T) concentrations in 118 boys aged 8 to 17.9 years were related to chronological age (CA), bone age (BA), genital development (G1–5+), pubic hair development (PH1–5 +) and mean testicular volume (MTV). A progressive rise in serum FSH, LH and T was noted in relation to CA, BA and all pubertal parameters studied. FSH showed an approximate twofold increase, LH an eight to tenfold increase and T a fourfold increase from pre-puberty through to full adult maturity. The FSH/LH ratio decreased with advancing CA, BA and pubertal development.     

Diagnosis of X-recessive Kallmann syndrome in early infancy

A 3-month-old infant presented with hypogonadism, a small penis and bilateral cryptorchidism. He showed an insufficient response of luteotropic hormone (LH) and follicle stimulating hormone (FSH) to luteotropic hormone releasing hormone (LHRH) and of testosterone to human chorionic gonadotrophin. The maternal uncle had hypogonadism and anosmia and also showed an impaired LH and FSH response to LHRH. MRI examination showed hypoplasia of the rhinencephalon in both cases. These findings in the son and brother of the clinically unaffected mother suggest X-linked recessive inheritance.     

Fish oil supplementation improves docosahexaenoic acid status of malnourished infants

AIM—To investigate whether the low docosahexaenoic acid (DHA) status of malnourished, mostly breast fed, Pakistani children can be improved by fish oil (FO) supplementation.
METHODS—Ten malnourished children (aged 8-30 months) received 500 mg FO daily for nine weeks. The supplement contained 62.8 mol% (314mg) long chain polyunsaturated fatty acids of the ω3 series (LCPUFAω3) and 22.5 mol% (112 mg) DHA. Seven FO unsupplemented children served as controls. Red blood cell (RBC) fatty acids were analysed at baseline and at the study end.
RESULTS—FO supplementation augmented mean (SD) RBC DHA from 2.27 (0.81) to 3.35 (0.76) mol%, without significantly affecting the concentrations of LCPUFAω6. Unsupplemented children showed no RBC fatty acid changes. One FO supplemented child with very low initial RBC arachidonic acid showed a remarkable increase from 4.04 to 13.84 mol%, whereas another with high RBC arachidonic acid showed a decrease from 15.64 to 10.46 mol%.
CONCLUSION—FO supplementation improves the DHA status of malnourished children. The supplement is apparently well absorbed and not exclusively used as a source of energy.

     

Treatment of persistent pubertal gynecomastia with dihydrotestosterone heptanoate

Four boys with persistent pubertal gynecomastia were given intramuscular dihydrotestosterone heptanoate (DHT-hp) at 2 to 4-week intervals for 16 weeks. By the end of treatment, breast size in all four boys had decreased 67% to 78%. Initial plasma levels of gonadotropins, estradiol, testosterone, and dihydrotestosterone (DHT) were normal. Mean plasma DHT concentration rose with the injections of DHT-hp, and remained elevated throughout the treatment period. Estradiol, LH, FSH, and testosterone decreased during treatment, as did 24-hour urinary LH and FSH. No regrowth of breast tissue was observed 6 to 15 months after treatment, although hormone concentrations had returned to near pretreatment values by 2 months after the last injection. DHT-hp has potential to be an effective medical therapy for persistent pubertal gynecomastia.