normal male pubertal development requires a timed activation of the pituitary gonadal axes and normal progression of sexual maturation through different stages . the two sexual maturation spurts characterized by sertoli and leydig cell proliferation during the antenatal and pubertal periods are considered important for normal pubertal development . clinical aberrations from this normal pattern of pubertal development are well described , i.e. , precocious or delayed pubertal development and hypogonadism . delay in pubertal onset and subsequent normal sexual maturation as in constitutional delay of growth and puberty ( cdgp ) is well known . the various factors attributed for pubertal delay include nutritional and hormonal factors , systemic diseases , familial , and unknown genetic and environmental factors . available literature from books and reviews on pediatric endocrinology indicates that delay in pubertal onset in the absence of systemic diseases beyond the age of 18 years is exceedingly rare . till 1991 , only one case of kallmann syndrome that had pubertal onset after 20 years age was described . recently , raivio et al . described 15 males diagnosed as hypogonadotropic hypogonadism after 18 years of age , who demonstrated increasing testicular volumes and improving sperm counts while on treatment . these authors believed that exposure to androgens may have in an unknown manner activated the hypothalamopituitary gonadal axis that was responsible for a late onset of puberty in these patients . they termed this phenomenon as a reversible form of hypogonadotropic hypogonadism . here , we describe nine males who presented at or after 18 years of age with lack of secondary sexual characters , and had onset of pubertal development while on androgen therapy . case observational study . we studied patients of idiopathic hypogonadotropic hypogonadism ( ihh ) , who had increase in testicular volume ( to at least 10 ml bilaterally ) while on androgen therapy diagnosis of ihh was made on the basis of clinical features ( testicular volume less than 6 ml ) , initial presentation after 18 years of age , low to normal levels of gonadotropins , low testosterone levels ( < 1 ng / ml ) , and normal sellar imaging . patients with evidence of systemic diseases , hypothyroidism , growth hormone ( gh ) deficiency , hyperprolactinemia , hypocortisolism , and history of treatment [ with human chorionic gonadotropin ( hcg ) or luteinizing hormone - releasing hormone ( lhrh ) therapy ] for hypogonadism were excluded from the study . the presenting complaints , anthropometry , pubertal status , and sex hormones at the first visit were noted from the medical records . these patients had been on testosterone therapy ( intramuscular testoviron injections containing testosterone undecanoate and testosterone succinate 100 mg intramuscularly every 21 days for 2 months and then 250 mg every 21 days ) . testosterone therapy was stopped when they demonstrated increase in testicular volumes to at least 10 ml bilaterally . reassessments were made after stopping androgen therapy for at least 5 months . at this visit , pubertal status was recorded , sex hormones were estimated , and semen examination was performed . after the re - evaluation visit , these patients were evaluated at a 3 - 6 monthly interval . luteinizing hormone ( lh ) , follicular stimulating hormone ( fsh ) , and testosterone levels were measured with radioimmunoassay ( kit supplied by diagnostics systems laboratories , inc . we studied patients of idiopathic hypogonadotropic hypogonadism ( ihh ) , who had increase in testicular volume ( to at least 10 ml bilaterally ) while on androgen therapy . diagnosis of ihh was made on the basis of clinical features ( testicular volume less than 6 ml ) , initial presentation after 18 years of age , low to normal levels of gonadotropins , low testosterone levels ( < 1 ng / ml ) , and normal sellar imaging . patients with evidence of systemic diseases , hypothyroidism , growth hormone ( gh ) deficiency , hyperprolactinemia , hypocortisolism , and history of treatment [ with human chorionic gonadotropin ( hcg ) or luteinizing hormone - releasing hormone ( lhrh ) therapy ] for hypogonadism were excluded from the study . the presenting complaints , anthropometry , pubertal status , and sex hormones at the first visit were noted from the medical records . these patients had been on testosterone therapy ( intramuscular testoviron injections containing testosterone undecanoate and testosterone succinate 100 mg intramuscularly every 21 days for 2 months and then 250 mg every 21 days ) . testosterone therapy was stopped when they demonstrated increase in testicular volumes to at least 10 ml bilaterally . reassessments were made after stopping androgen therapy for at least 5 months . at this visit , pubertal status was recorded , sex hormones were estimated , and semen examination was performed . after the re - evaluation visit , these patients were evaluated at a 3 - 6 monthly interval . luteinizing hormone ( lh ) , follicular stimulating hormone ( fsh ) , and testosterone levels were measured with radioimmunoassay ( kit supplied by diagnostics systems laboratories , inc . details of pubertal status and sex hormones at the initial visit and reassessments made after stopping androgen therapy for 5 months are given in table 1 . one patient had a brother with similar problem , but complete clinical details were not available . clinical details of patients showing reversibility of idiopathic hypogonadotropic hypogonadism the pre - therapy testicular volumes ranged from 3 to 6 ml and testosterone levels ranged from 0.02 to 0.39 ng / ml . all patients had been on at least 5 months of testosterone therapy . post - testosterone testicular volumes ranged from 10 to 20 ml and testosterone levels ranged from 0.9 to 8.1 ng / ml . semen examination done post - testosterone therapy demonstrated sperm counts varying from 15 to 96 millions / ml . all these patients have been followed further for an average period of 18 ( 4 - 33 ) months after discontinuation of testosterone therapy . ihh is a clinical entity characterized by lack of pubertal development , inappropriately low levels of gonadotropins , and absence of pituitary lesion on imaging . the characteristic male phenotype described is a tall male with eunuchoidal proportions , small testis , and absence of sperm counts . partial forms of hypogonadotropic hypogonadism presenting with incomplete and/or arrested pubertal development have also been described . some males with hypogonadism diagnosed during adolescence however , onset of puberty / reversal of the hypogonadotropic state beyond 18 years of age is exceedingly rare . anecdotal cases of reversal of hypogonadotropic hypogonadism in patients with kallmann syndrome have been reported . described a family with mutation in fibroblast growth factor receptor 1 gene , presenting as reversible kallmann syndrome , delayed puberty , and isolated anosmia . ribeiro et al . reported a kal1 gene mutation in a patient with reversible kallmann syndrome . recently , raivio et al . described 15 males who developed pubertal features while receiving treatment for hypogonadotropic hypogonadism . these males presented at or after 18 years of age , with absent ( n = 6 ) to partial ( n = 9 ) puberty . testicular volumes increased from 8 ml to 16 ml , testosterone levels increased , and spermatogenesis was documented while on hormonal therapy . they proposed that exposure to sex steroids in an unknown manner may have activated the hypothalamopituitary gonadal axis . some subjects in the present cohort had had testicular volumes ranging from 4 to 6 ml , thereby indicating a partial activation of the hypothalamic gonadal axis . there was development of secondary sexual characters after 18 years of age , while on androgen therapy . our present cohort was homogeneous in terms of the therapy used , since all patients were on testosterone therapy . in the study by raivio et al . , of 15 patients , 3 patients received gnrh and 7 had been on a mixed regimen of gonadotropins or gnrh  agents known to increase the testicular volume . testosterone is known to suppress the hypothalamopituitary gonadal axis and thereby inhibit the sertoli cell / tubular proliferation . in a group of 59 patients with hypogonadotropic hypogonadism , testicular volumes remained significantly low ( 4.31  1.8 ml ) after 4 years of testosterone therapy and testicular volumes increased to 14 ml in the subgroup receiving hcg therapy ( 14  2.0 ml ) . in the present study , androgens seem to have a stimulatory effect on the maturation of the hypothalamic gonadal axis . this situation is analogous to xy males with cah ( congenital adrenal hyperplasia ) where true precocious puberty occurs possibly due to sex steroid priming of the hypothalamus . a short course of androgens is also known to stimulate the latent pituitary gonadal axis in patients with cdgp . the progression of sexual maturation after stopping androgens in the present group of patients was heterogeneous . two patients had adult testicular volumes ( 15 - 20 ml ) and seven patients had pubertal testicular volumes though subnormal ( 10 - 12 ml ) . post - therapy testosterone levels were normal in one patient ( 8.1 ng / ml ) , low normal in five patients ( 3.2 - 4.6 ng / ml ) , and low ( 0.9 , 1.1 , and 2.7 ng / ml ) in three patients . such a heterogeneous pubertal development with testicular volumes ranging from 7.5 to 25 ml , testosterone levels ranging from 2.16 to 5.7 ng / ml , and sperm counts ranging from 0.3 to 152  10 millions / cc was also reported by raivio et al . the present cohort had onset / progression of pubertal development while on androgen therapy . sexual maturation was heterogeneous with normal , low normal , to low androgen levels 6 months after stopping androgen therapy . exposure to sex steroids at a timed appearance is required for normal sexual maturation a delayed androgen exposure may be able to initiate a pubertal spurt in some hypogonad patients after 18 years of age ; however , gnrh activity is either suboptimal or may decay with passage of time . a similar postulation for the premature termination of gonadal function has been described in patients with acquired hypogonadotropic hypogonadism . delay in pubertal onset in the absence of pituitary masses or systemic diseases after 18 years of age is rare . our present study indicates that pubertal development can occur in patients presenting with hypogonadotropic hypogonadism with normal sellar imaging , normal body mass index ( bmi ) , and absence of systemic diseases after 18 years of age .
background : onset of puberty in boys usually occurs by 14 years of age . some boys may exhibit delayed sexual maturation till about 17 - 18 years of age . however , pubertal onset beyond 18 years of age is exceedingly rare.materials and methods : patients diagnosed as idiopathic hypogonadotropic hypogonadism ( ihh ) who had onset of puberty ( increase in testicular volume > 10 ml ) while on androgen therapy were studied . 
 these patients were evaluated prospectively.results:there were nine subjects that were included in the study . 
 the pre - therapy testicular volumes ranged from 3 to 6 ml . 
 luteinizing hormone ( lh ) levels increased from 1.2  0.96 to 2.8  1.0 
 iu / l , follicular stimulating hormone ( fsh ) levels increased from 1.5  0.79 to 3.5  1.9 iu / l , and testosterone increased from 0.36  0.16 to 3.4  2.1 ng / ml . 
 three out of nine patients had testosterone levels below 3 ng / ml.conclusion : our present study indicates that pubertal development can occur in patients presenting with hypogonadotropic hypogonadism after 18 years of age 
 . however , acquired pubertal status may be subnormal