Male hypothalamic hypogonadism: induction of spermatogenesis by subcutaneous pulsatile gonadotrophin-releasing hormone

Six male patients (aged 21-34 years) with isolated hypothalamic hypogonadism were given subcutaneous pulses of gonadotrophin-releasing hormone every 90 min for 14-74 weeks. The therapy produced an increase in testicular volume (4 patients) and a rise in serum luteinizing hormone, follicle-stimulating hormone, and testosterone levels in every patient. Motile sperm developed in 3 patients after a mean of 17 weeks, but were not seen in other patients who were less sexually developed after a mean of 31 weeks of therapy. Computerized tomography scans of the pituitary fossa revealed an empty sella in 4 patients and a partially empty sella in 2. Subcutaneous pulsing of gonadotrophin-releasing hormone is a simple and safe way of inducing spermatogenesis, but it is more likely to be successful in patients whose pubertal development is otherwise near completion. Previous human chorionic gonadotrophin and/or testosterone treatment does not interfere with and may benefit subsequent gonadotrophin-releasing hormone therapy.     

Hypothalamic hypogonadism: induction of ovulation and pregnancy by subcutaneous pulsatile injections of gonadotrophin-releasing hormone

5 female patients with isolated hypothalamic hypogonadism were given subcutaneous pulses of gonadotrophin-releasing hormone (GnRH), 2.5-15 micrograms every 90 min, for 2-6 months by means of an automated pump. This treatment produced an increase in serum LH, FSH, and estradiol levels in 4 patients, all of whom became pregnant. The estradiol levels failed to rise in 1 patient, in spite of an adequate LH and FSH response, and a subsequent biopsy showed evidence of primary ovarian failure in addition to the hypothalamic deficit. We conclude that subcutaneous pulsatile GnRH administration is a simple, safe, and relatively inexpensive way to induce ovulation in patients with hypothalamic hypogonadism.     

Pulsatile gonadotropin-releasing hormone treatment of men with idiopathic hypogonadotropic hypogonadism

OBJECTIVES/METHODS: To induce testicular growth and spermatogenesis, 11 patients with idiopathic hypogonadotropic hypogonadism were treated with long-term subcutaneous pulsatile gonadotropin-releasing hormone (GnRH) administration. Three patients had a history of undescended testes. Patients who did not respond to therapy with a sufficient increase in serum testosterone or spermatogenesis were offered additional injections with hCG or, after discontinuation of GnRH, either combined therapy with hCG and hMG or recombinant FSH. RESULTS: During treatment testicular volume and serum levels of FSH, LH and testosterone increased. Semen analysis revealed the presence of spermatogenesis in 9 of the 11 patients (8 on GnRH alone and in 1 when hCG/hMG was subsequently instituted), and 7 pregnancies have resulted thus far. CONCLUSION: Pulsatile GnRH therapy is a well-tolerated and effective therapy for the induction of spermatogenesis in some men with idiopathic hypogonadotropic hypogonadism. It appears that a significant fraction of them should be treated for a minimum of 1-2 years to maximize testicular growth and achieve spermatogenesis. Cryptorchidism was a negative prognostic factor.     

Problems in the use of pulsatile gonadotrophin-releasing hormone for the induction of puberty

The induction of puberty by the administration of subcutaneous 15-micrograms pulses of gonadotrophin-releasing hormone (GnRH) every 90 min during day and night is described in two patients. Too rapid an induction of puberty occurred in one patient while initial progress in the other ceased after the development of pituitary desensitisation. We have attributed these results to the use of GnRH pulses in too high amplitude, and we suggest a more appropriate dose regimen.     

Short-term pulsatile administration of luteinizing hormone releasing hormone in male adolescents with multiple idiopathic pituitary hormone deficiencies

In order to define both level and severity of defect in patients with idiopathic multiple pituitary hormone deficiencies (MPHD) and to find out which patient might benefit from pulsatile LHRH substitution therapy, the effect of short-term pulsatile LHRH infusion in 6 affected male adolescents was studied. Controls were 9 boys with constitutional delay of puberty (CD). During a spontaneous nocturnal plasma profile LH and FSH levels were prepubertal with little evidence of pulsatile secretory LH activity in all MPHD patients. During short-term pulsatile LHRH stimulation (36 h), however, all showed a significant rise in mean LH and FSH levels (p less than 0.0001). Linear regression analysis revealed significant continuous increases of FSH (p less than 0.001) in all patients and of LH (p less than 0.01) in all but one patient. These changes were not accompanied by an increase of testosterone, androstenedione and DHAS levels. Since all MPHD patients showed steadily increasing gonadotropin levels if stimulated in a pulsatile manner, we conclude that the defect might only in part be located at the pituitary level. Long-term pulsatile substitution therapy with LHRH is likely to be successful in these patients as has been demonstrated in patients with known hypothalamic defect.     

Changes in plasma inhibin A levels during sexual maturation in the female chicken and the effects of active immunization against inhibin alpha-subunit on reproductive hormone profiles and ovarian function

Inhibins and activins are firmly implicated in the control of pituitary FSH secretion and ovarian follicular development in mammals. As in mammals, inhibin A and activin A are expressed in the preovulatory follicles of birds, and a defined ovulation cycle for inhibin A has recently been demonstrated in the laying hen. To investigate further the role of inhibin-related proteins in developing pullets, circulating concentrations of inhibin A, inhibin B, total immunoreactive inhibin alpha-subunit (ir-alpha), activin A, LH, FSH, and progesterone were measured from the juvenile state through to sexual maturity in 22 birds. In the 11 birds assigned to control groups, plasma inhibin A levels were low from 7 to 13 wk of age rising about threefold to a peak at Week 19 after which levels fell slightly to a plateau level characteristic of adult hens. Plasma inhibin A levels were negatively correlated with FSH (r = -0. 33; P: < 0.001) and positively correlated with progesterone (r = 0. 67; P: < 0.001) and ir-alpha (r = 0.53; P: < 0.001). Plasma ir-alpha levels were much higher than inhibin A levels although the relative differences varied with age. Plasma levels of inhibin B and activin A were below assay detection limits at all times. The remaining group of 11 birds was actively immunized (IMM) against a synthetic chicken inhibin alpha-subunit peptide (amino acids 1-26). The IMM generated circulating antibodies that bound native bovine inhibin A but altered neither plasma FSH nor progesterone levels relative to control birds at any stage of development nor the timing of first oviposition in week 19. Apart from a transient decline 1 wk after primary IMM, plasma LH concentrations did not differ from controls. Comparison of the numbers and size-class distribution of ovarian follicles at 29 wk showed an approximate twofold increase in the number of 8- to 9.9-mm-diameter follicles (control; 1.82 +/- 0.44 vs. IMM; 3.91 +/- 0.89; P: < 0.05), a size class that corresponds to follicles that have just joined the preovulatory hierarchy. The numbers of growing follicles in other size-classes and the sizes of hierarchical F(1)-F(7) follicles were not altered by IMM. However, the number of postovulatory follicles increased (control 3.73 +/- 0. 20 vs. IMM 5.55 +/- 0.28; P: < 0.01), and significantly more (P: < 0. 02) immunized hens laid two eggs within a 24-h period on at least one occasion (control 1 of 11 vs. IMM 9 of 11). The IMM increased (P: < 0.05) activin A content of F(1) and F(2) theca layers and decreased (P: < 0.05) activin A content in F(3) and F(4) granulosa layers, raising the possibility of a local intraovarian role of activin in mediating the response to IMM. These findings support a role for inhibin A in regulating the entry of follicles into the preovulatory hierarchy in the chicken, although further studies are required to establish the mechanism by which inhibin IMM increases the rate of follicle selection and ovulation without raising plasma FSH.     

A patient with hypogonadotropic hypogonadism successfully treated by long-term pulsatile administration of luteinizing hormone-releasing hormone

A male patient with hypogonadotropic hypogonadism has been treated by pulsatile administration lf luteinizing hormone-releasing hormone (LHRH) (20-25 micrograms, every 2 hours, sc) for 4 years 6 months. His plasma testosterone (T) concentration began to increase after 4 weeks of treatment and reached the normal range in week 5. He showed complete secondary sexual development after 1 year of treatment. His sperm count was normalized after 1 year of treatment. He was married after 29 months of therapy, and has a healthy male child. Blood type tests showed his paternity of the child. During the long duration of pulsatile LHRH therapy, his gonadotropin secretion has been stimulated by LHRH and his T level has been maintained with no observable side effects. There are no other reports of patients treated by pulsatile LHRH injection for such a long duration, but finding in this patient indicated that long-term pulsatile LHRH therapy is a useful and safe method for treatment of hypothalamic hypogonadotropic hypogonadism.     

Normal sequence of the gonadotropin-releasing hormone gene in patients with idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) results from absent or greatly diminished secretion of GnRH. Defects in the GnRH gene have been identified in an animal model of IHH and have been hypothesized as a possible basis for GnRH deficiency in humans. In this study, we used the polymerase chain reaction to clone and sequence the coding regions, promoter, and 3' untranslated tract of the GnRH genes from both alleles of four unrelated patients with IHH. One of the patients studied is a member of a kindred in which X-linked inheritance has been excluded by father-to-son transmission of the disease. No DNA sequence mutations were found. We conclude that most cases of IHH in humans do not involve mutations in the GnRH gene and are presumably caused by mutations at one or more other genetic loci that are required for normal function of GnRH-producing neurons.     

Circadian and pulsatile variations in plasma levels of inhibin, FSH, LH and testosterone in adult Murrah buffalo bulls

The present study investigated pulsatile and circadian variations in the circulatory levels of inhibin, gonadotrophins and testosterone. Six adult buffalo bulls (6 to 7 yr of age) were fitted with indwelling jugular vein catheters, and blood samples were collected at 2-h intervals for a period of 24 h and then at 15-min interval for 5 h. Plasma concentrations of inhibin, FSH, LH and testosterone were determined by specific radioimmunoassays. Plasma inhibin levels in Murrah buffalo bulls ranged between 0.201 to 0.429 ng/mL, with a mean of 0.278 +/- 0.023 ng/mL. No inhibin pulses could be detected during the 15-min sampling interval. Plasma FSH levels ranged between 0.95 to 3.61 ng/mL, the mean concentration of FSH over 24 h was 1.66 +/- 0.25 ng/mL. A single FSH pulse was detected in 2 of 6 bulls. The LH levels in peripheral circulation ranged between 0.92 to 9.91 ng/mL, with a mean concentration of 3.33 +/- 1.02 ng/mL. Pulsatility was detected in LH secretion with an average of 0.6 pulses/h. Plasma testosterone levels in 4 buffalo bulls ranged from 0.19 to 2.99 ng/mL, the mean level over 24 h were 1.34 +/- 0.52 ng/mL. Testosterone levels in peripheral circulation followed the LH secretory pattern, with an average of 0.32 pulses/h. The results indicate parallelism in inhibin, FSH and LH, and testosterone secretory pattern. Divergence in LH and FSH secretory patterns in adult buffalo bulls might be due to the presence of appreciable amounts of peripheral inhibin.     

Influence of amphetamines on plasma corticosteroid and growth hormone levels in man

Plasma fluorogenic corticosteroid and immunoreactive growth hormone levels rose significantly after the intravenous administration of methylamphetamine to healthy young men at various times of the day. The rise in corticosteroids was most pronounced in the evening and was accompanied by an increase in circulating levels of immunoreactive corticotrophin. Oral dexamphetamine also resulted in significant rises in plasma corticosteroids but not in growth hormone. These hormonal changes were accompanied by evidence of mild central stimulation. Though they may be part of an associated and non-specific response, it is more likely that they represent specific effects of amphetamines on centres in the hypothalamus or midbrain controlling secretion of corticotrophin and growth hormone releasing factors.     

Changes in peripheral inhibin levels and follicular development following treatment of buffalo with PMSG and Neutra-PMSG for superovulation

Fourteen buffalo were synchronized by administration of a prostaglandin (PG) salt Lutalyse in a double injection schedule, with a single intramuscular (im) injection of 25 mg at Day -13, followed by 30 mg and 20 mg im 12 h apart on Day 0 of the experiment. The 30-mg PG injection was designated as 0 h of the experiment. Group I animals (n = 4) received saline and served as the controls, while animals in Groups II and III (n = 5 each) received PMSG (2500 IU im at -48 h. Group III animals were administered 5 ml Neutra-PMSG intravenously at 60 h. Blood samples were collected every 48 h from Day -12 to Day -4, every 24 h from Day -4 to Day 0, every 3 h from Day 1 to Day 4 and every 24 h from Day 5 to Day 10 of experiment for the measurement of peripheral plasma inhibin concentrations by RIA. The number of large follicles (> 10 mm diameter) in animals of Groups II and III was assessed by ultrasonography on Days -2, -1, 0, 1, 2, 5 and 7 of the experiment. Treatment with PMSG of Group II animals resulted in a significant increase (P < 0.05) in plasma inhibin concentrations over that of control animals of Group I at 24 to 99 h, with a peak inhibin concentration of 1.01 +/- 0.31 ng/ml at 48 h. Treatment with Neutra-PMSG in Group III animals caused a significant reduction (P < 0.05) in the peripheral inhibin concentrations at 84 to 120 h and in the number of large unovulated follicles at 168 h compared with that in Group II animals. Peripheral inhibin levels in Group III animals came down to those of Group I after 21 h of Neutra-PMSG treatment. These results suggest that treatment of buffalo with PMSG for superovulation causes a marked rise in peripheral inhibin concentrations. Administration of Neutra-PMSG after PG treatment reduces the peripheral inhibin concentrations and the number of large unovulated follicles.     

Testicular responsiveness to long-term administration of hCG and hMG in patients with hypogonadotrophic hypogonadism

Steroidogenic responsiveness and amelioration of sperm number and motility following long-term intramuscular hCG and hMG administration were evaluated in 18 males with hypogonadotrophic hypogonadism (HH). The patients consisted of 13 patients with isolated gonadotrophin deficiency (IGD) and 5 patients hypophysectomized at an early or middle pubertal period. Basal serum levels of testosterone and 17 beta-estradiol were within prepubertal range in all patients before the treatment. Serum testosterone levels reached the normal adult male levels within 12-24 months of the treatment in only 2 of 7 younger patients and 1 of 6 older patients with IGD, whereas in all hypophysectomized patients serum levels of both testosterone and 17 beta-estradiol increased to the levels found in normal adult males within 6 months of the treatment. The mean peak levels of serum testosterone and 17 beta-estradiol, respectively, during the treatment were 2.1 +/- 0.8 (SD) ng/ml and 10.8 +/- 4.9 (SD) pg/ml in younger patients with IGD, 1.4 +/- 0.9 ng/ml and 9.7 +/- 5.1 pg/ml in older patients with IGD and 6.0 +/- 1.2 ng/ml and 34.2 +/- 14.8 pg/ml in hypophysectomized patients. Quantitative improvement in both sperm density and sperm motility were found in 4 of 7 younger patients, 1 of 6 older patients with IGD and all hypophysectomized patients, but only 3 of hypophysectomized patients (3 of 18 patients) could become fertile.     

Long-term results with growth hormone therapy in idiopathic hypopituitarism

More than 30 years after its introduction, growth hormone (GH) treatment is well established in children with GH deficiency. Nevertheless, the long-term results of this therapy, expressed as height, are generally considered unsatisfactory. We report on results obtained in a group of GH-deficient children who were treated with daily injections of recombinant GH within the first 5 years of life and who reached an adult height very close to their target height. The full catch-up growth to the target height demonstrated in these patients suggests that replacement therapy should be started early and continued until adulthood. Height at onset of puberty is an important variable which might significantly influence the adult height. The significant and prolonged influence of birth weight on growth response to GH therapy underlines the important role of fetal growth in planning early treatment of GH-deficient children.     

Pharmacological doses of oxytocin affect plasma hormone levels modulating glucose homeostasis in normal man

Pharmacological doses of oxytocin administered in basal conditions evoked a rapid surge in plasma glucose and glucagon levels followed by a later increase in plasma insulin and adrenaline levels. The effects of oxytocin on plasma glucagon and adrenaline levels were potentiated by hypoglycemia. When the endogenous pancreas secretion was suppressed by cyclic somatostatin (150 micrograms/h) and exogenous glucagon (3.5 micrograms/h) and insulin (0.2 mU/kg.min) were both replaced, oxytocin (0.2 U/min) evoked a transient but significant increase in plasma glucose levels suppressing the glucose infusion rate (GIR) in the first 60 min. On the contrary at higher insulin infusion rate (0.6 mU/kg.min) plasma glucose levels and GIR remained unaffected throughout the study. Oxytocin seems also to potentiate glucose-induced insulin secretion as evidenced by hyperglycemic glucose clamp. In conclusion, pharmacological doses of oxytocin seem to exert a prevalent hyperglycemic effect by a combined action at the liver site (as glycogenolytic agent) and at the endocrine pancreas (as a stimulatory agent of A cell secretion).