Absent Pubertal Development Research Articles

Application of gonadotropin releasing hormone in hypogonadotropic hypogonadism--diagnostic and therapeutic aspects

Puberty is the result of reactivation of the gonadotropin releasing hormone (GnRH) pulse generator resulting in an increasing release of GnRH by the hypothalamus, which stimulates the gonadotropic cells of the pituitary to synthesize and secrete LH and FSH. Hypogonadotropic hypogonadism (HH) is often the result of GnRH deficiency. The clinical picture is characterized by the absence of pubertal development and infertility. It is difficult to differentiate HH from delayed puberty since low gonadotropin and low testosterone levels are found in both conditions. We hypothesized that long-term GnRH administration may differentiate between the two conditions by a difference in the increase of gonadotropins, the idea being that in normal delayed puberty the pituitary of the patient has been primed with GnRH during the fetal and early postnatal period. Seventeen adolescents suspected of having hypogonadotropic hypogonadism were treated with pulsatile GnRH for 7 days. At the present time, the diagnosis of these patients is known and the results of the long-term GnRH stimulation have been evaluated according to the present diagnosis. The results show that the increase in gonadotropins following GnRH treatment is similar in both conditions. Therefore, at a prepubertal age a normal delayed puberty cannot be distinguished from hypogonadotropic hypogonadism using long-term GnRH stimulation. Long-term pulsatile GnRH treatment is a physiological therapy for the induction of puberty. Unlike testosterone it has the advantage of stimulation of testicular growth and fertility, as well as virilization, in males. We have treated 68 male patients with HH with pulsatile GnRH. The results show testicular growth and virilization in all the patients and spermatogenesis in 58 patients. Wearing a portable pump is cumbersome. However, the patients were very motivated and adapted very easily to this inconvenience. When spermatogenesis had developed, GnRH treatment was changed to human chorionic gonadotropin (hCG) administration 1-2 times per week intramuscularly or subcutaneously. During hCG therapy spermatogenesis was maintained or even improved. At least ten patients fathered children. Pulsatile GnRH cannot distinguish between a normal delayed puberty and a hypothalamic defect in still prepubertal patients. Pulsatile GnRH offers an appropriate way to initiate testicular growth including virilization and fertility in males with hypogonadotropic hypogonadism.

Endocrine complications of high-dose therapy with stem cell transplantation.

Evaluations of endocrine function following hematopoietic cell transplantation demonstrate that the endocrine function abnormalities observed are related to the type of transplant preparative regimen received. Children given high dose cyclophosphamide (CY) only have normal thyroid function, normal growth and development. Children who received a busulfan (BU) plus CY preparative regimen usually have normal thyroid function, normal prepubertal growth, delayed or absent pubertal development, and blunted post-pubertal growth. Recipients of preparative regimens containing total body irradiation may be anticipated to have some thyroid dysfunction, impaired growth rates and delayed or absent pubertal development. Post-pubertal teens and young adults are likely to have gonadal function recover if they received a preparative regimen with CY only but are likely to have primary gonadal failure if they received a preparative regimen with BU or total body irradiation. Individuals whose gonadal function becomes normal have become parents of normal children. All patients who receive a marrow transplant should be followed long-term for development of endocrine function abnormalities.

Giant Seminoma in a Patient With 5α-Reductase Type 2 Deficiency

A 49-year-old Japanese phenotypic female was referred for a giant inguinal mass. The parents and maternal half brother were reported to be phenotypically normal, and there was no family history of male pseudohermaphroditism or consanguinity. The parents were divorced shortly after the patient was born, and the patient was reared by her mother. However, at presentation the mother had been deceased for 30 years and, thus, detailed familial information, such as place of parental birth, was not available. Physical examination revealed a giant mass in the left inguinal region and a small testis-like mass in the right inguinal region. The patient had a masculine habitus with no breast development, moderate pubic hair (Tanner stage 3), an enlarged clitoris (5 cm. in stretched length) and a blind ending vagina. The karyotype was 46 XY in all 30 lymphocytes analyzed. Endocrine data were consistent with 5 reductase type 2 deficiency. Basal serum luteinizing hormone was 16.5 IU/l. (adult male normal 1.0 to 8.4), folliclestimulating hormone 56.5 IU/l. (1.0 to 10.5), testosterone 14.7 nmol./l. (11.2 to 50.0), 5 -dihydrotestosterone 0.38 nmol./l. (0.87 to 2.60) and testosterone-to-5 -dihydrotestosterone ratio 39 (12 to 20). She also appeared to manifest abnormal gender role behavior, as has often been reported with this condition.2 Although the patient was raised as a female and recognized herself as a female, she had never sought medical evaluation despite the absence of pubertal development and menarche, and had remained single and was living with another woman. After obtaining informed consent, mutational analysis was performed for the SRD5A2 gene encoding steroid 5 reductase type 2. In brief leukocyte genomic DNA was amplified with the primers for all 5 exons and their flanking introns of SRD5A2 by polymerase chain reaction, and the products were subjected to direct sequencing from both directions.2 Consequently a homozygous C16T transversion resulting in a substitution of the sixth glutamine codon by stop codon (Q6X) was identified. This transversion was absent in a total of 100 normal individuals. The patient underwent surgical exploration for the bilateral masses. Macroscopically the large left mass was an 11 10 8 cm. solid tumor with extensive necrosis and focal hemorrhage, and the small right mass was an atrophic testis 2 to 3 ml. in volume. There was no discernible invasion of adjacent tissues or metastasis to the retroperitoneal lymph nodes. Wolffian structures were well developed, and mullerian structures were absent. Microscopically the solid tumor showed typical findings of seminoma, and the right testis displayed dysgenetic features, such as hyalinized seminiferous tubules, Leydig cell hyperplasia and defective spermatogenesis without carcinoma in situ (see figure). Subsequently the patient received local irradiation therapy. Estrogen supplementation therapy was not started because of her advanced age and refusal. She was healthy at 12-month followup.

Adult-onset idiopathic hypogonadotropic hypogonadism — A treatable form of male infertility: Nachtigall L.B.; Boepple P.A.; Pralong F.P.; Crowley W.F. Jr. USA New Engl J Med 1997 336/6 (410–415)

Background Men with isolated gonadotropinreleasing hormone (GnRH) deficiency typically present with an absence of pubertal development. We describe an adult-onset form of idiopathic hypogonadotropic hypogonadism that develops after puberty. Methods We studied 10 men (age, 27 to 57 years) with normal sexual maturation, idiopathic infertility, sexual dysfunction, low serum testosterone concentrations, and apulsatile secretion of luteinizing hormone on frequent blood sampling. All the men had otherwise normal anterior pituitary hormone secretion and sellar anatomy. We compared the results of semen analyses and measurements of testicular volume, serum testosterone, inhibin B, and gonadotropins in these men with the results in 24 men with classic GnRH deficiency before and during GnRHreplacement therapy and in 29 normal men of similar age. Results Serum gonadotropin concentrations in the men with adult-onset GnRH deficiency were similar before and during pulsatile GnRH administration to those in the men with classic GnRH deficiency. However, as compared with men with classic GnRH deficiency, men with adult-onset hypogonadotropic hypogonadism had larger mean ( � SD) testicular volumes (18 � 5 vs. 3 � 2 ml, P � 0.001), serum testosterone concentrations (78 � 34 vs. 49 � 20 ng per deciliter [2.7 � 1.2 vs. 1.7 � 0.7 nmol per liter], P � 0.004), and serum inhibin B concentrations (119 � 52 vs. 60 � 21 pg per milliliter, P � 0.001). Treatment with GnRH reversed the hypogonadism and restored fertility in each of the five men who received long-term therapy. Conclusions The recognition of adult-onset hypogonadotropic hypogonadism in men as a distinct disorder expands the spectrum of GnRH deficiency and identifies a treatable form of male infertility. (N Engl J Med 1997;336:410-5.) ©1997, Massachusetts Medical Society.