This is a Kallman syndrome (hypogonadotropic hypogonadism + olfactory disturbance). Triptorelin is a GnRH agonist, which by continuous action reduces FSH and LH, and is used in sex hormone-dependent cancers, as well as precocious puberty. Bromocriptine is a dopaminergic agonist used in hyperPRL (he has normal PRL), pituitary tumors... We stay between 1 and 3. To induce testicular maturation, pulsatile GnRH with pump, hCG or FSH+hCG can be used. LH is not used as a treatment, it would be stimulated by intermittent GnRH.

A 22-year-old boy with hyposmia presents lack of development of secondary sexual characteristics and infertility. Bilateral testicular volume of 4 mL. Analytically, EST-I 1.2 U/L (vn 5-15); LH 0.6 U/L (vn 3-15); testosterone 100 ng/dL (vn 300-1200), prolactin normal. State your proposed treatment to achieve fertility:

Monthly intramuscular administration of triptorelin.

Intramuscular administration of FSH and LH once a week.

[Effect of pulsatile GnRH therapy on pituitary-testicular axis function in male patients with pituitary stalk interruption syndrome].

To evaluate the efficacy of pulsatile gonadotropin-releasing hormone (GnRH) therapy in male patients with pituitary stalk interruption syndrome (PSIS). Fourteen male PSIS patients, who had received subcutaneous pulsatile GnRH therapy for at least four weeks at Peking Union Medical College Hospital from April 2014 to September 2015, were included in the study. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone level, testicular volume and sperm in ejaculation were measured. After treatment for four weeks, subjects with serum LH≥1.24 U/L were classified as"good response group", and others were classified as"poor response group". All patients were born by breech delivery and presented with absent pubertal development. Laboratory findings showed combined pituitary hormone deficiency in all patients. Pituitary stalk interruption syndrome was diagnosed based on MRI findings. Totally 11 out of 14 patients showed good response to pulsatile GnRH therapy. Their LH level increased from 0.32 (0.15, 0.61) U/L to 4.34(2.52, 7.39)U/L(P<0.001), FSH from 0.84 (0.30, 1.50) U/L to 7.12 (4.53, 10.09) U/L(P<0.001); serum testosterone level from 0 (0, 0.45) nmol/L to 2.46 (0.56, 11.45) nmol/L (P=0.004) and testicular volume from 2.0 (2.0, 4.0) ml to 4.0 (3.0, 6.0) ml (P=0.005). Sperm was detected in seminal samples after treatment for 8 weeks in two patients and for 12 weeks in one patients. Three out of 14 patients showed poor response to pulsatile GnRH therapy. Pulsatile GnRH therapy can effectively establish the pituitary-testicular axis function for most patients with pituitary stalk interruption syndrome, indicating enough reserve of gonadotrophs in the pituitary.

Desogestrel

of FSH and testosterone levels. A previous study by the same authors found that increasing the dosage of desogestrel from 300 μg/day to 450 μg/day resulted in no further suppression of gonadotropin concentrations. The addition of a low dose of 50 or 100 mg/week intramuscular testosterone enanthate after 3 weeks increased testosterone levels and further suppressed LH and FSH levels, to the limits of assay detection (i.e., to undetectable or near-undetectable levels), in both the 150 μg/day and 300 μg/day desogestrel groups. Upon cessation of treatment, levels of LH, FSH, and testosterone all recovered to baseline values within 4 weeks.

Testosterone administration inhibits gonadotropin secretion by an effect directly on the human pituitary.

Testosterone (T) administration slows LH pulse frequency in man, presumably by an effect on the hypothalamic GnRH pulse generator, but it also may have a direct action on the pituitary. To determine if T does indeed affect gonadotropin secretion by acting directly on the pituitary, we studied the effect of T on GnRH-stimulated gonadotropin secretion. Six men with hypogonadotropic hypogonadism were treated with physiological doses of GnRH (5 micrograms every 2 h, sc by automatic infusion pump) for 6 weeks. Once their gonadotropin levels were normal, the men received a supraphysiological dosage of T enanthate (200 mg, im, weekly for 8 weeks) in addition to GnRH. They then received GnRH alone for a final 8-week period. Blood sampling was performed every 10 min for 8 h at the end of each of the three study periods. T administration suppressed the mean serum LH level to about 50% of the value during GnRH alone [18 +/- 2 (+/- SE) vs. 37 +/- 2 micrograms/L; P less than 0.05] and suppressed the mean serum FSH level to about 30% of the value during GnRH alone (39 +/- 6 vs. 128 +/- 28 micrograms/L; P less than 0.05). Eight weeks after stopping T, while continuing GnRH alone, serum LH and FSH levels were similar to those at the end of the first period of GnRH administration. The mean LH response to GnRH was reduced during T administration (17 +/- 3 micrograms/L) compared to that during the initial period of GnRH alone (31 +/- 4 micrograms/L; P less than 0.05). Serum T and estradiol levels were in the low normal range after GnRH alone before T administration (11 +/- 2 nmol/L and 105 +/- 17 pmol/L, respectively) and increased to just above the normal adult ranges after 8 weeks of T administration (36 +/- 5 nmol/L and 264 +/- 49 pmol/L, respectively). These results demonstrate that T and/or its metabolites inhibit LH and FSH secretion by a GnRH-independent mechanism, probably directly on the pituitary gland, in man.

Hypogonadism, galactorrhoea and hyper-prolactinaemia: Evaluation of pituitary gonadotrophins reserve before and under bromocriptine.

Twenty patients with hypogonadism (19 women with amenorrhoea and 1 man with impotence and infertility), galactorrhoea and hyper-prolactinaemia (range: 36 to 344 ng/ml) were studied. The radiological study of the sella turcica, including in all cases hypocycloidal tomograms, allowed classification of the patients into 3 groups: group I (n = 4) had a grossly enlarged sella turcica, group II (n = 12) had localized alterations indicating the probable existence of a prolactin-secreting microadenoma ("microdeformation") while group III patients presented no radiological abnormality. Before treatment, all the patients were submitted to a complete evaluation of the function of their anterior pituitary, including the LH and FSH responses to iv administration of Gn-RH. All the group I patients had low basal LH levels and a blunted response to Gn-RH. The basal LH and in response to Gn-RH were normal in most of the group II patients and in all of the group III patients. An exaggerated FSH response to Gn-RH was observed in 6/12 patients with microdeformation (group II) but not in groups I and III patients. A low LH and a blunted LH response to Gn-RH is highly suggestive of the existence of a pituitary prolactin-secreting adenoma in case of amenorrhoea and hyper-prolactinaemia patients; a normal response does not however rule out such a diagnosis. The reasons for a exaggerated FSH response to Gn-RH in patients with suspected prolactin-secreting microadenoma remain to be investigated though this pattern can also occur in other cases of amenorrhoea. Hence the Gn-RH test might contribute to the assessment of the hypothalamo-pituitary axis of patients with hyper-prolactinaemia. Six patients treated for 4 months with bromocriptine (CB-154) were submitted to re-evaluation of their pituitary gonadotrophins reserve. All the women experienced restoration of menses with 39 days of treatment and the male patient regained potency. It was observed that bromocriptine treatment and subsequent normalized prolactin levels in the 4 group II women tested were associated with normalization of their previously exaggerated FSH response to Gn-RH; LH responses were also diminished in these cases. These data are compatible with the hypothesis that hyper-prolactinaemia per se could interfere with the endogenous secretion of Gn-RH at the hypothalamic level. In one patient with grossly enlarged sella turcica and a previous lack of an LH and FSH response to Gn-RH, bromocriptine treatment restored a normal gonadotrophins response, confirming that, in this case, the alteration of this response was indeed due to a prolonged lack of endogenous Gn-RH secretion.

Gonadotropin-releasing hormone insensitivity

Diagnosis When suspected on the basis of the clinical presentation or physical findings, the diagnosis of GnRH insensitivity should be confirmed biochemically. The diagnosis requires the following findings: The demonstration of prepubertal serum concentrations of sex steroid hormones (serum testosterone less than 100 ng/dL [3.5 nmol/L] in males or serum estradiol less than 20 pg/mL [73 pmol/L] in females). Inappropriately low or normal serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations (usually less than 4 to 5 international units/L) rather than the high concentrations expected with primary gonadal failure. Otherwise normal anterior pituitary function.

Clinical and hormonal response to short-term intermittent versus continuous oral bromocriptine in hyperprolactinemic women.

OBJECTIVE -- To determine if intermittent oral bromocriptine administration could be a useful therapeutic alternative in infertile hyperprolactinemic women. DESIGN -- Open, randomized and prospective study. SETTING -- Outpatient infertility clinic of a third-level medical institution. PATIENTS -- Fourteen low-income women, 23 to 36 years of age with anovulatory infertility (1-13 years in duration) secondary to hyperprolactinemia (>35 ng/mL). Endocrine profile ruled out anovulation of other origin. INTERVENTIONS -- After a control period of 30 days, seven women (group 1) received daily oral bromocriptine (2.5-10.0 mg/day) continuously during two consecutive 30-day periods (T-1 and T-2), and seven women (group 2) received oral bromocriptine only from day 1 to 15 of each 30-day period of treatment. Morning blood samples were drawn similarly during the three periods on days 6 to 8, 13 to 15, and 21 to 23. MAIN OUTCOME MEASURES -- FSH, LH, and prolactin were determined in all samples, estradiol only in samples of days 6 to 8 and 13 to 15, and progesterone exclusively between days 21 and 23. Mean serum prolactin levels during the control period were similarly elevated in groups 1 and 2. A marked decrease occurred during period T-1 (P < .004) and further during period T-2 (P < .05) in both groups, but at no time were significant intergroup differences documented. During the control period all women had a serum progesterone < 3.0 ng/mL (<9.54 nmol/L); during period T-2 it was > or = 3.0 ng/mL in three and five women of groups 1 and 2, respectively. Over the following 10 months of treatment, two and three normal pregnancies and deliveries ensued in groups 1 and 2, respectively. CONCLUSION -- The intermittent use of oral bromocriptine may indeed be a useful therapeutic approach in treating infertile hyperprolactinemic women.

Prolactin regulation of testosterone secretion and testes growth in DLS rams at the onset of seasonal testicular recrudescence.

Our objective was to test the hypothesis that prolactin (PRL) acts at both the pituitary and testis levels to regulate testosterone secretion in the adult ram. The focus was on the mid-regression to mid-redevelopment stages of a photoperiod-condensed 'seasonal' testicular cycle. DLS rams (six per group) were given daily s.c. injections of bromocriptine (4 mg) or vehicle during the entire period. Serum PRL concentration in control rams peaked at 103.4+/-22.1 ng/ml in late regression and then steadily declined (P<0.01) to 19.5+/-4.3 ng/ml, whereas PRL in treated rams was always < or =4.0 ng/ml. Suppression of PRL tended (P<0.10) to increase the amplitude of natural LH pulses (transition stages) or reduce the number of LH receptors in the testis (regressed stage), although neither change disturbed testosterone levels in peripheral blood. These subtle changes were accompanied by significant (P<0.05) alterations in the capability of the pituitary to release LH (85% more) and of the testes to secrete testosterone (20% less). These effects of PRL were unmasked when rams were given highly stimulative i.v. injections of GNRH (single 3 microg dose) and NIH-oLH-S24 (three 5 microg doses given 20 min apart) respectively. PRL insufficiency also appeared to slow down the 'seasonal' rise in FSH secretion and slightly delayed (2 weeks) the times when the testes began to grow and were first significantly (P<0.05) enlarged from the regressed state. We conclude that PRL is an important part of the intricate regulation of the pituitary-gonadal system in moderately seasonal DLS rams.

Gonadotropin-releasing hormone agonist

Agonists do not quickly dissociate from the GnRH receptor. As a result, initially there is an increase in FSH and LH secretion (so-called "flare effect"). Levels of LH may increase by up to 10-fold, while levels of testosterone generally increase to 140 to 200% of baseline values. However, after continuous administration, a profound hypogonadal effect (i.e. decrease in FSH and LH) is achieved through receptor downregulation by internalization of receptors. Generally this induced and reversible hypogonadism is the therapeutic goal. During the flare, peak levels of testosterone occur after 2 to 4 days, baseline testosterone levels are returned to by 7 to 8 days, and castrate levels of testosterone are achieved by 2 to 4 weeks. Following cessation of exogenous GnRH agonist it takes 5 to 8 days before normal gonadotropin secretion is completely restored.

Hypogonadotropic hypogonadism

Diagnosis The clinical presentation of HH depend on the time of onset as well as the severity of the defect. Diagnostic tests to measure GnRH levels are difficult. This is because GnRH is confined within hypophyseal portal system and has a short half-life of 2–4 minutes. GnRH levels are thus checked indirectly via LH and FSH levels which will be totally or partially absent in HH. Exogenous GnRH can be used as a diagnostic tool. If the patient has hypothalamic GnRH deficiency, LH and FSH will gradually appear in response to the exogenous GnRH but in pituitary cases of HH, a minimal response will be generated. Typically, CHH is diagnosed in adolescence due to a lack of pubertal development, but it can be possible to diagnose in male neonates. Clinical presentations of CHH involve an absence of puberty by 18 years of age, poorly developed secondary sexual characteristics, or infertility.

Gynecology_Novak

Brain imaging (MRI is the gold standard) to exclude  Pituitary microadenoma  Pituitary macroadenoma  Other abnormal brain mass Hypothyroidism  Exclude secondary causes  Treat condition  Supplement with thyroid hormone if indicated  Spontaneous ovulation will occur when thyroid function normalizes  Treat underlying condition  When prolactin normalizes, spontaneous ovulation should occur Anovulation Normal or high day 3 FSH and LH Ovarian disorders (see Figure 30.3) Low LH, FSH, TSH, GH, ACTH High serum prolactin levels Abnormal TSH or T4Low FSH, LH, E2 Hypothalmic disorders Thyroid disease Hyperprolactinemia Panhypopituitarism Assess and treat condition Repeat test to exclude false positive Elevated prolactin If a pituatary microadenoma is diagnosed  Bromocriptine or cabergoline to normalize prolactin level  Spontaneous ovulation should occur when prolactin is normal Anorexia  Medical and psychiatric assessment  Treat condition  Aim to increase BMI to allow spontaneous

Gonadotropin-releasing hormone (GnRH) analog suppression renders polycystic ovarian disease patients more susceptible to ovulation induction with pulsatile GnRH.

Pulsatile GnRH administration consistently restores normal reproductive hormone levels and ovulation in women with hypogonadotropic hypogonadism, but is less effective in those with polycystic ovarian disease (PCOD). We pharmacologically created a hypogonadotropic condition with a GnRH analog (GnRH-A) in six women with PCOD to investigate the role of deranged gonadotropin secretion in PCOD and to improve the response to pulsatile GnRH ovulation induction. Before GnRH and GnRH-A treatment the women with PCOD had increased LH pulse frequency [one pulse every 55 +/- 2 (+/- SE) min; P less than 0.05] and LH pulse amplitude (10.9 +/- 1.4 U/L; P less than 0.05) compared to normal women in the follicular phase of their menstrual cycle. Each PCOD woman completed one cycle of pulsatile GnRH administration for ovulation induction before (pre-A cycles; n = 6) and one or two cycles after (post-A cycles; n = 9) GnRH-A administration [D-Ser(tBu)6-Des,Gly10-GnRH; 300 micrograms, sc, twice daily for 8 weeks]. Pulsatile GnRH (5 micrograms/bolus) was given at 60-min intervals using a Zyklomat pump. Daily blood samples were drawn during the pulsatile GnRH ovulation induction cycles for the determination of serum LH, FSH, estradiol (E2), progesterone, and testosterone, and pelvic ultrasonography was done at 1- to 4-day intervals. Mean (+/- SE) serum LH levels were elevated during the pre-A cycle (49.2 +/- 3.1 IU/L) and decreased to normal levels during the post-A cycles (19.6 +/- 1.4 IU/L; P less than 0.0001). Mean testosterone concentrations were lower during the post-A cycles [88 +/- 2 ng/dL (3.1 +/- 0.1 nmol/L)] than during the pre-A cycles [122 +/- 3 ng/dL (4.2 +/- 0.1 nmol/L); P less than 0.0001]. In the follicular phase of the post-A cycles E2 levels were significantly lower [81 +/- 5 pg/mL (300 +/- 20 pmol/L) vs. 133 +/- 14 pg/mL (490 +/- 50 pmol/L); P less than 0.0001], preovulatory ovarian volume was smaller (24.6 +/- 2.0 vs. 31.4 +/- 2.4 cm3; P less than 0.01), and the FSH to LH ratio was higher (0.56 +/- 0.03 vs. 0.16 +/- 0.01) than in the pre-A cycle, suggesting more appropriate function of the pituitary-gonadal axis. Excessive LH and E2 responses to pulsatile GnRH administration in the early follicular phase of the pre-A cycle were abolished in the post-A cycles.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of hypogonadotropic hypogonadal male patients with the luteinizing hormone-relasing hormone (LH-RH) anolog D-Ser(TBU)6 EA10 LH-RH: transient disappearance of gonadotropin stimulation.

We have studied the effect of prolonged treatment with a long-acting luteinizing hormone-releasing hormone (LH-RH) analog (D-Ser-(TBU)6 EA10 LH-RH in six patients with isolated gonadotropin deficiency. Before treatment, all subjects responded to LH-RH (100 microgram intravenously [IV]); one responded immediately, and five after 5 daily infusions of LH-RH (200 microgram). Treatment by LH-RH analog (348 microgram every 2 days with a nasal spray for 90 or 120 days) is only efficient for 1 month; a consistent increase in serum LH and a slight increase in testosterone (T) were observed in all patients, but no increase of serum follicle-stimulating hormone (FSH) was detectable. Then a paradoxical effect appeared: LH and T levels returned to the basal values. Moreover, this treatment induced refractoriness of the pituitary to LH-RH for several months after the end of treatment. The appearance of antibodies to LH-RH and LH-RH analog was eliminated. A pituitary response was obtained in three patients when a new LH-RH stimulation was repeated 7 and 11 months after the end of treatment. The mechanism of this pituitary desensitization is discussed.

Spontaneous and GnRH-provoked gonadotropin secretion and testosterone response to human chorionic gonadotropin in adolescent boys with thalassaemia major and delayed puberty.

To elucidate whether the cause of sexual maturation arrest in thalassaemia is of gonadal or pituitary etiology, 10 males with thalassaemia and delayed puberty and 10 with constitutional delay of growth and pubertal maturation (CSS) were extensively studied. Their spontaneous nocturnal gonadotropin secretion and gonadotropin response to intravenous 100 micrograms gonadotropin-releasing hormone (GnRH) were evaluated. Circulating testosterone concentration and clinical response were evaluated after 3 days, 4 weeks and 6 months of intramuscular administration of human chorionic gonadotropin (HCG) (2500 U/m2/dose). Thalassaemic boys had significantly lower circulating concentrations of testosterone compared to those with constitutional delay of growth and sexual maturation (CSS) at the same pubertal stage. Short- and long-term testosterone response to administrations of HCG was markedly decreased in thalassaemic boys. After 6 months of HCG administration 50 per cent (5/10) of the boys did not show significant testicular enlargement or genital changes. Despite the low circulating concentrations of testosterone, none of the patients had high basal or exaggerated gonadotropin response to gonadotropin releasing hormone (GnRH) stimulation. Luteinizing hormone (LH) peak responses to GnRH were significantly lower as compared to controls. Follicle-stimulating hormone (FSH) peak responses to GnRH did not differ among the two study groups. The mean nocturnal LH and FSH secretion was significantly decreased in all thalassaemic boys as compared to boys with CSS at the same pubertal stage (testicular volume). These data proved that hypogonadotropic hypogonadism is the main cause of delayed/failed puberty in adolescents with thalassaemia major. MRI studies revealed complete empty sella (n = 5), marked diminution of the pituitary size (n = 5), thinning of the pituitary stalk (n = 3) with its posterior displacement (n = 2), and evidence of iron deposition in the pituitary gland and midbrain (n = 8) in thalassaemic patients, denoting a high incidence of structural abnormalities (atrophy) of the pituitary gland. Moreover, in many of the thalassaemic boys, the defective testosterone response to long-term (6 months) HCG therapy denoted significant testicular atrophy and/or failure secondary to siderosis. It appears that testosterone replacement might be superior to HCG therapy in these patients. This therapy should be introduced at the proper time in these hypogonadal patients to induce their sexual development and to support their linear growth spurt and bone mineral accretion.

[Effects of a new analogue of LH-RH, D-Ser(TBU)6- EA10-LH-RH, on gonadotropin liberation in males (author's transl)].

Effects on the secretion of gonadotropins by D-Ser (TBU)6-EA10-LH-RH were investigated in 7 male volunteers without known endocrine disturbances. One week after subcutaneous injection of 100 mug of LH-RH the probands were given 5 mug of the LH-RH analogue subcutaneously into the abdominal wall. LH, FSH and testosterone concentrations were estimated in the serum and compared with each other at varying intervals after each injection. LH-RH caused a marked increase of the LH content in serum after 20 minutes with a maximum after 40 minutes. The effect of the analogue occurred with a delay. After 40 minutes an LH level was reached which still persisted 6 hours later. Contrary to LH there were considerable individual differences in serum FSH levels. In the initial phase after injection of LH-RH and LH-RH analogue that increase of the FSH level in serum was almost parallel. However, the analogue showed a marked depot effect. Serum concentrations of testosterone showed no significant changes after administration of the releasing hormones. D-Ser(TBU)6-EA10-LH-RH is approximately 20 times effective as LH-RH. A dose of 5 mug is effective for 6-8 hours.

Testicular leydig cell tumor presenting as primary infertility.

A 29-year old male and his wife presented with an 18 month history of primary infertility. History and initial investigations suggested no major female pathologic component but a semen analysis revealed azoospermia. There was no history of any sexual dysfunction and neither partner was receiving any medication. Clinical examination revealed normal secondary sexual characteristics. Both testicles were of normal consistency with a volume of approximately 15 ml but a 4 x 2 cm mass was palpable at the lower pole of the left testis. Laboratory investigations revealed: serum testosterone 37.1 nmol/l (NV:10.0-38.0 nmol/l), LH<0.3 U/L (NV:3.0-12.0 U/L), and FSH <0.1 IU/L (NV:3.0-11.0 U/L). Serum b-HCG, aFP, LDH, oestradiol and inhibin levels were within the normal range. A repeated semen analysis confirmed azoospermia. Testicular ultrasound demonstrated a well-defined hypoechoic mass, measuring 31 x 23 x 17 mm and containing several flecks of calcification, arising from the lower pole of the left testis. A left orchidectomy was performed. Macroscopical histopathological examination revealed a single firm dark brown nodule 2.8 cm in diameter arising from the lower pole of the testis. The tumor distended the capsule of the testis without extending through it. Microscopical examination was consistent with a Leydig cell tumor. Computerised tomography of the chest, abdomen and pelvis was normal. Six months later, laboratory investigations revealed a serum testosterone of 14.3 nmol/l, an LH of 5.4 U/L and an FSH of 4.3 U/L, respectively. A repeated semen analysis was normal: volume 1.8 ml(2-10 ml), count 124 x 10(6) (20-350 x 10(6)), motility 80%(>60%), abnormal forms <15%(<15%). Three months later his wife was pregnant. In summary, our patient presented with azoospermia, secondary to a Leydig cell tumor, which was reversible after removal of the tumor.

Effect of a new LH-RH analogue (D-Ser(TBU)6-EA10-LH-RH) on gonadotrophin and gonadal steroid secretion in men.

The effect of a new analogue of the gonadotrophin-releasing hormone LH-RH, D-Ser(TBU)6-EA10-LH-RH, on the secretion of LH, FSH, as well as testosterone, oestradiol, HGH, prolactin, TSH, and cortisol was studied in normal men. The same subjects were injected intravenously in 4-day intervals with 1.0, 2.5, 5.0, and 10.0 mug of this substance. A significant LH but no FSH release was seen after doses of 1.0 and 2.5 mug LH-RH analogue, while after 5.0 and 10.0 mug dose-dependent increases of LH and imposed elevations of FSH were observed. Peak levels of LH were reached after 30 min, those of FSH after intravenous injection after 120 min. LH and FSH remained elevated for 8-10 h. LH peak levels after 5 mug of LH-RH analogue were comparable to those seen after injection of 100 mug of the decapeptide LH-RH. Following the release of LH and FSH after doses of 5.0 and 10.0 mug LH-RH analogue, there was a late stimulating effect in testosterone and oestradiol secretion. HGH, TSH, prolactin, and cortisol were not influenced by the LH-RH analogue.

Further acquisitions on gonadal function in bromocriptine treated hyperprolactinemic male patients.

The diurnal variation of plasma total and free testosterone (tT and fT) and the gonadotropinemic response to LH-RH were evaluated in a group of hyperprolactinemic impotent males with pituitary microprolactinoma before and during therapy with bromocriptine, a well known dopamine agonist drug. Before treatment, basal levels not only of tT but also of fT were decreased and the diurnal variation of both tT and fT was absent. Moreover, the LH-RH test showed a delay in the LH response peak, together with normal basal levels of LH. Bromocriptine therapy caused normalization of both the secretion response of LH to LH-RH and of the secretion pattern of tT and of fT (basal levels and diurnal variation) besides a significant decrease in PRL levels and an improvement in sexual function. The possible effects of high plasma levels of PRL at various levels of the hypothalamus-pituitary-testicular axis are discussed.

Kallmann syndrome

Treatment for both males and females with KS/CHH normally consists of one of three options which can be used for both hormone replacement therapy and/or fertility treatment. Sex hormone replacement (testosterone or oestrogen & progesterone). Gonadotropin therapy (medications that replicate the activity of FSH and LH). GnRH pulsatile therapy. Hormone replacement therapy The method and dose of treatment will vary depending on the individual being treated. Initial treatment is normally made with lower doses in younger patients in order to develop the secondary sexual characteristics before adult doses are reached.

Comparison of detection of normal puberty in boys by a hormonal sleep test and a gonadotropin-releasing hormone agonist test.

The magnitude of sleep-related gonadotropin rise required to activate pubertal gonadal function is not established. Our objective was to determine the normal relationship between sleep-related pubertal hormone levels and pituitary-testicular responsiveness to a GnRH agonist (GnRHag) test across the pubertal transition. DESIGN/SETTING AND PARTICIPANTS: We conducted a prospective study in a General Clinical Research Center with healthy 9- to 15-yr-old volunteer boys. INTERVENTIONS included overnight blood sampling followed by leuprolide acetate injection (10 μg/kg). LH, FSH, and testosterone levels were evaluated. LH levels during sleep and post-GnRHag rose steadily during the late prepubertal years. Sleep peak LH correlated highly with the LH response to GnRHag across groups (r = 0.913). A sleep peak LH level of at least 3.7 U/liter predicted pubertal testicular activation with 100% accuracy. LH of at least 14.8 and at least 19.0 U/liter 4 h after GnRHag, respectively, predicted puberty with 100% sensitivity/94% specificity and 100% specificity/94% sensitivity. Overweight pubertal boys had transiently prolonged responses to GnRHag. FSH rose during both waking and sleeping hours during the prepubertal years, and all pubertal boys had an FSH level of at least 0.9 U/liter awake and at least 1.2 U/liter asleep. Sleep LH was more closely related than FSH to testicular size. These data suggest that a critical LH level during sleep (≥3.7 U/liter) heralds the onset of pubertal virilization and that this level is predictable by LH of at least 14.8-19 U/liter 4 h after GnRHag. These data also suggest that LH stimulation of testicular androgen production plays a role in stimulating testicular tubule growth once a critical level of FSH is achieved.

[The effects of bromocriptine on anovulatory patients with high LH and euprolactinemia].

It is well known that an acute administration of Bromocriptine (dopamine agonist) suppresses the serum LH level either in normal women or in women with polycystic ovary syndrome, in whom the serum LH level is elevated. The present study was carried out to examine the effectiveness of Bromocriptine on anovulatory women with a high LH level (serum LH greater than 30 mIU/ml). Bromocriptine was administered for 3 months, 5 mg daily, to 9 anovulatory women with euprolactinemia (serum PRL less than 25 ng/ml). Ovulation was observed by their BBT charts. Before and after the treatment of Bromocriptine, FSH, LH and PRL secreting capacities were tested by LHRH and TRH injection. Also, estrone, estradiol and testosterone levels were measured before and after the Bromocriptine administration. Resting levels of LH, FSH and PRL were 45.4 +/- 11.0 mIU/ml, 11.4 +/- 3.0 mIU/ml, and 14.3 +/- 4.7 ng/ml (M +/- SD), respectively, before the treatment. As a result of the treatment, the LH level was markedly decreased to 27.3 +/- 14.5 (M +/- SD, P less than 0.05), and PRL decreased to 3.76 +/- 4.2 ng/ml (M +/- SD, P less than 0.005). On the other hand, FSH did not show a marked change. The responsiveness of LH to LHRH before the treatment showed a marked increase, which was suppressed by Bromocriptine. However, FSH showed no change. The responsiveness of PRL to TRH was suppressed by Bromocriptine. Serum estrone, estradiol and testosterone levels before the treatment were 115.5 +/- 76.7 pg/ml, 93.7 +/- 61.0 pg/ml and 0.809 +/- 0.209 ng/ml (M +/- SD), respectively, which showed no significant change after the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Aromatization mediates testosterone's short-term feedback restraint of 24-hour endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle-stimulating hormone secretion in young men.

The present clinical study examines the neuroregulatory hypothesis that feedback restraint of LH and FSH secretion by testosterone requires in vivo aromatization. To test this postulate, we prospectively and randomly assigned 47 healthy young men to 1 of 5 parallel short-term (5-day) double-blind interventions with: 1) placebo; 2) high-dose ketoconazole (KTCZ, 400 mg orally 4 times daily) to block both Leydig-cell and adrenal steroidogenesis; 3) KTCZ and transdermal testosterone delivery (7.5 mg daily); 4) KTCZ and transdermal estradiol (0.05 mg daily); or 5) KTCZ, testosterone, and the selective and potent aromatase inhibitor, anastrazole (5 mg orally twice daily). Blood was sampled every 10 min for 27 h on the last day of intervention to quantitate 24-h mean spontaneous and 3-h post-GnRH-stimulated (100 ng/kg iv bolus) LH and FSH release. KTCZ administration lowered the serum total testosterone concentration markedly from (mean +/- SEM) 423 +/- 57 ng/dL (15 +/- 2.0 nmo/L) during placebo ingestion to 58 +/- 8.6 ng/dL (2.0 +/- 0.3 nmol/L) (P < 10(-3)). Transdermal androgen addback along with KTCZ blockade increased testosterone levels to 607 +/- 57 ng/dL (21 +/- 2.0 nmol/L). KTCZ exposure alone drove a 3-fold increase in serum LH concentrations (P < 10(-3)) and a 2.5-fold rise in FSH secretion (P = 0.015), as assessed by high-specificity immunoradiometric assays. Concomitant transdermal testosterone (or estradiol) delivery repressed the elevated secretion of both LH and FSH to mid-normal baseline values. A 3-fold administration of anastrazole, KTCZ, and testosterone completely opposed exogenous testosterone's suppression of 24-h LH and FSH secretion. Anastrazole coadministration likewise abolished testosterone-dependent inhibition of 3-h GnRH-stimulated LH and FSH release. In summary, assuming the specificity of anastrazole's inhibition of aromatase activity, we conclude that circulating testosterone in healthy men curtails endogenously driven as well as exogenous GnRH-stimulated LH and FSH secretion conditional on its in vivo aromatization.

[Increased and prolonged release of lh and fsh on intravenous administration of a synthetic analogue of lh-rh [d-ser(tbu)6-ea10-lh-rh] in healthy men of various age groups (author's transl)].

Healthy male subjects of various age groups respond to the administration of D-Ser(TBU)6-EA10-LH-RH, an analogue of LH-RH substituted in positions 6 and 10, by a prolonged and increased release of LH and FSH. Increased serum concentrations of LH and FSH were observed 20 minutes after intravenous administration of the compound. Maximum concentrations of LH and FSH were seen after 60, and 60 to 240 minutes, respectively. Serum concentrations of both gonadotropins remained elevanted for up to 8 hours after the administration of 10 microgram of the LH-RH analogue. A dose response relationship was observed with regard to the serum concentrations of LH and FSH over the range of 1.25 to 5.0 microgram of the LH-RH analogue. The administration of 10 or 20 microgram of the compound, however, did not cause a further rise in plasma FSH, although the release of LH was further enhanced.

Polyestradiol phosphate

Antigonadotropic effects PEP has antigonadotropic effects due to its estrogenic activity. It has been found to suppress testosterone levels in men by 55%, 75%, and 85% at intramuscular dosages of 80, 160, and 240 mg every 4 weeks, respectively. A single intramuscular injection of 320 mg PEP in men has been found to suppress testosterone levels to within the castrate range (< 50 ng/dL) within 3 weeks. This was associated with circulating estradiol levels of just over 200 pg/mL. The suppression of testosterone levels that can be achieved with PEP is equal to that with orchiectomy. However, to achieve such concentrations of testosterone, which are about 15 ng/dL on average, higher concentrations of estradiol of around 500 pg/mL were necessary. This was associated with a dosage of intramuscular 320 mg PEP every four weeks and occurred by 90 days of treatment. However, 240 mg PEP every four weeks has also been reported to eventually suppress testosterone levels in the castrate range.

Results of three-times-per-week long-term administration of a luteinizing hormone-releasing hormone (LHRH) analog, D-Ser-(TBU)6-LHRH-(EA)10 in primary amenorrhea.

The effectiveness of a luteinizing hormone (LH)-releasing hormone (LHRH) analog, D-Ser-(TBU)6-LHRH-(EA)10 (Hoe 766), applied intranasally in a 3 days-per-week regimen, was assessed in four patients with hypogonadotropic or normogonadotropic primary amenorrhea by measuring LH, follicle-stimulating hormone (FSH), and estradiol (E2) levels before and 4 hours after its application and by observing the clinical effects of these hormones on the genital tract. The LH response increased progressively over the first 21 days (nine applications) in three of the four patients; it was subsequently reduced but never abolished throughout the study, which was terminated with the 25th application on the 59th day. Basal values of E2 increased until the 12th to 14th day (fifth or sixth application) and then showed a definite decline despite the continuing increase in LH response. FSH release attained a maximum by the second to fourth application and its magnitude of response remained remarkably stable thereafter. The clinical response did not correspond to the serum levels of E2. It is postulated that the development of LH unresponsiveness is due to desensitization of the receptors by the analog. The poor response of the genital tissues to the normal levels of E2 and the subsequent decrease in E2 levels, which occurred despite increasing LH responsiveness, are attributed to an inhibitory action of the analog on E2 biosynthesis in the ovary and on E2 receptors in the genital organs.

Meta-Analysis of Paediatric Patients with Central Precocious Puberty Treated with Intramuscular Triptorelin 11.25 mg 3-Month Prolonged-Release Formulation
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A meta-analysis was undertaken to assess the effect of triptorelin 11.25 mg 3-month prolonged-release formulation in central precocious puberty (CPP). All available clinical studies with triptorelin 11.25 mg were included. The primary outcome was the proportion of children with suppressed luteinising hormone (LH) response (peak LH ≤3 IU/L) to the gonadotrophin-releasing hormone (GnRH) test 3 months after triptorelin 11.25 mg injection. Secondary outcomes included: the proportion with suppressed peak LH response at 6 months and the proportion with suppressed peak follicle-stimulating hormone (FSH) response (≤3 IU/L), suppressed oestradiol (≤20 pmol/L) in girls or suppressed testosterone (≤30 ng/dL) in boys at 3 months. 153 children (13 boys, 140 girls) were included. The proportion with a suppressed peak LH response to the GnRH test was 87.6% (95% CI: 81.3-92.4, p < 0.0001, for a proportion >70%) and 92.8% (95% CI: 87.5-96.4, p < 0.0001, for a proportion >70%) at 3 and 6 months, respectively. FSH peak, oestradiol, and testosterone were suppressed in 86.7% (95% CI: 79.1-92.4), 97.1% (95% CI: 91.6-99.4), and 72.7% (95% CI: 39.0-94.0) of children at 3 months, respectively. Triptorelin 11.25 mg 3-month formulation is efficacious in suppressing LH peak and other gonadal hormones and in slowing the progression of CPP in children.
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Pituitary and testicular response to LH-RH and to a long-acting analogue (D-leu-6-LH-RH-ethylamide).

The LH, FSH and testosterone response to 50 microgram i.v. LH-RH and to 2.5, 5.0, 10.0, and 20.0 microgram i.m. D-Leu-6-LH-RH-ethylamide was studied in 6 subjects with normogonadotrophic, idiopathic oligozoospermia. All injections were given between 8:00 and 9:00 a.m. at weekly intervals. Blood samples were collected before and 30 and 45 minutes after injection of LH-RH, and before and 2, 4, 6, 12, and 24 hours after D-Leu-6-LH-RH-ethylamide injections. Serum levels of LH, FSH, and testosterone were measured by triplicate by R.I.A. LH and FSH responses to LH-RH showed peak values at 30 minutes, whereas following injections of D-Leu-6-LH-RH-ethylamide, maximal values were recorded between 4 and 6 hours and were higher than those obtained with LH-RH. A significant rise of serum testosterone levels was observed after all stimuli, with peak values 45 minutes after LH-RH and 4 to 6 hours after D-Leu-6-Lh-RH-ethylamide injections. The testosterone levels obtained following LH-RH and different doses of the analogue did not differ significantly from one another. The same sequence of maximal LH and FSH values was obtained after injections of LH-RH and of D-Leu-6-LH-RH-ethylamide, particularly at doses of 10.0 and 20.0 microgram. This suggests that the gonadotrophin response to these agents would be a true reflection of the individual mode of pituitary response.

Reduction of follicle-stimulating hormone (FSH) secretion in FSH-producing pituitary adenoma by bromocriptine.

An FSH-secreting pituitary adenoma was demonstrated in a 32-yr-old man who presented with unilateral optic atrophy without any clinical or laboratory evidence of hypogonadism. Semen analysis was normal, although basal FSH levels were markedly elevated (greater than 80 mIU/ml). He had normal plasma LH levels and no other detectable endocrine abnormalities. Administration of GnRH elicited delayed and sustained FSH and brisk LH responses. Administration of TRH resulted in TSH and PRL responses and unexpected FSH and LH elevations. Two surgical operations resulted in temporary reduction of plasma FSH levels, but it increased later concomitant with CT demonstration of tumor growth. After pituitary irradiation, no reduction in FSH levels occurred. A single dose of 5 mg bromocriptine elicited a significant reduction in FSH levels from 137 to 64 mIU/ml. Long term treatment with 15 mg/day bromocriptine resulted in further reduction of FSH level, to 36.4 mIU/ml, without any change in tumor size. This finding implies that bromocriptine could be an adjunctive therapy or an alternative to other modes of treatment in patients with these rare tumors.

Pituitary response to steroid replacement therapy in fertile, subfertile and infertile stallions after castration.

Recent studies in our laboratory investigating plasma gonadotrophin concentrations before and after castration indicate that the hypothalamic-pituitary axis is not the original site of dysfunction in stallions with idiopathic infertility. In the present study, fertile, subfertile and infertile stallions were subjected to replacement therapy with oestradiol and testosterone 1 year after castration to investigate hypothalamic-pituitary axis function further. Fertile (n=5), subfertile (n=3) and infertile (n=2) castrated stallions of Light horse breeds, aged 11-23 years, were given either oestradiol cypionate or testosterone propionate for 28 days during the breeding season. Oestradiol cypionate in cottonseed oil (30 mg; 6 mg ml(-1)) was administered i.m. at 2 day intervals starting in May for 28 days. Eight weeks after the last oestradiol cypionate injection, testosterone propionate in vegetable oil (85 mg; 8.5 mg ml(-1)) was administered i.m. at 2 day intervals for 28 days. Heparinized blood samples were taken from the jugular vein three times a week from 3 weeks before the start of oestradiol cypionate treatment until 4 weeks after the last testosterone propionate injection. Saline or 25 microg GnRH in 1 ml saline were administered to the stallions on days 24 and 25, respectively, of the 28 day steroid treatments. Jugular blood samples were collected periodically through a catheter from 60 min before saline or GnRH injection until 420 min after injection. The plasma samples were stored at -20 degrees C until analysed for plasma LH, FSH, oestradiol and testosterone concentrations by validated radioimmunoassay. Exogenous steroid treatment increased plasma oestradiol and testosterone concentrations to concentrations close to normal circulating values (oestradiol: 49 pg ml(-1); testosterone: 1.3 ng ml(-1)) in all the groups. There were no significant differences in plasma LH or FSH concentrations among the groups during any of the treatment periods. Oestradiol treatment significantly increased (P < 0.05) LH concentrations, whereas testosterone treatment decreased LH concentrations, although the difference was not significant. Oestradiol treatment significantly decreased FSH concentrations (P < 0.05), whereas testosterone treatment significantly increased FSH concentrations (P < 0.05). There were no differences in LH and FSH responses to GnRH challenge among the three groups of stallions. In conclusion, the results of the present study indicate that the hypothalamic-pituitary axes in these subfertile and infertile stallions were not the original sites of dysfunction. Further studies at the testicular level are required.

Inhibitory effects on gonadotrophin secretion and gonadal function in men during chronic treatment with a potent stimulatory luteinizing hormone-releasing hormone analogue.

Long-term treatment with the potent and long-acting stimulatory luteinizing hormone-releasing hormone (LRH) analogue D-Ser(TBU)6-EA10-LRH was given to 4 healthy men to study its effects on pituitary gonadotropin secretion and gonadal function. Five micrograms of the LRH agonist was self-administered sc once daily over 17 weeks. Weekly basal blood samples were obtained for determination of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolacting (PRL) and testosterone. The gonadotrophin responses to the LRH analogue were also determined during the treatment period. LRH tests were performed after treatment. Seminal fluid specimens were collected during and after treatment. A reduction of the basal serum gonadotrophin and testosterone levels were observed during the treatment period. The FSH and LH responses to the analogue were also diminished. After discontinuation of treatment the gonadotrophin and testosterone concentrations returned to pre-treatment levels within a week. The PRL levels and the seminal fluid specimens did not show any significant changes during the study period. The results suggest that chronic treatment with D-Ser(TBU)6-EA10-LRH has an inhibitory effect on the pituitary gonadotrophin secretion in healthy men. It seems likely that the reduced testosterone level is secondary to the diminished gonadotrophin secretion.

Nitric oxide regulation of gonadotrophin secretion in prepubertal heifers1.

Mechanisms responsible for the pulsatile release of gonadotrophin secretion in prepubertal heifers are not fully known. We have shown that an excitatory amino acid agonist, N-Methyl-D,L-aspartic acid (NMA), induces an immediate release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in prepubertal heifers. Nitric oxide (NO) has also emerged as an important regulator of LH release in rats. This study was designed to test the role of NO in the regulation of gonadotrophin release as well as the possible mediation by NO of the effects of NMA and gonadotrophin releasing hormone (GnRH) on gonadotrophin secretion in heifer calves. In experiment 1, four groups of five prepubertal heifers (33 weeks old) received one of the following treatments: (1); N-G-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor, 35 mg/kg, i.v., once); (2) NMA (4.7 mg/kg, i.v., once); (3) L-NAME+NMA (as above); and (4) Vehicle (saline, i.v.). All heifers in all groups were also challenged with a bolus injection of GnRH (10 ng/kg, i.v., once). Blood samples were collected every 15 min for 10 h. L-NAME was injected after the first blood sample, NMA after 2 h and GnRH after 6 h of blood sampling. Administration of L-NAME alone, suppressed the spontaneous pulses of LH (P<0.04). Heifers in the NMA group responded with a significantly greater LH release than did the heifers in the L-NAME+NMA group (P<0.05). Following the GnRH challenge, heifer calves treated with L-NAME or NMA had higher LH pulse responses than the controls (P<0.05). In a second experiment, four groups of five heifer calves (34 weeks old) were given one of the following treatments: (1) L-NAME (as above); (2) L-arginine, a NO precursor (ARG, 100 mg/kg/h, i.v. drip infused for 6 h starting 2 h after first blood sample was taken); (3) L-NAME+ARG (as above); and (4) Vehicle (saline i.v. bolus and drip for 6 h). Blood samples were taken every 10 min for 8 h. Administration of L-NAME suppressed the pulsatile release of LH and FSH (P<0.05). Compared to the control group, infusion of ARG by itself did not change the pattern of LH secretion (P>0.05); however, in heifers given L-NAME, ARG restored a normal pattern of LH pulses, similar to the control values (P>0.05). It was therefore concluded that NO is involved in the regulation of LH, and possibly FSH, secretion and that NO may mediate, at least in part, the stimulatory effects of NMA on LH, and to some extent FSH, release. The responses to GnRH led us to suggest that NO may have inhibitory effects on the pituitary and NMA may have increased pituitary sensitivity to GnRH.

Bromocriptine effects on plasma luteinizing hormone and its responses to gonadotropin-releasing hormone in normal men.

Secretory changes in plasma pituitary luteinizing hormone (LH) after administration of a dopaminergic drug were studied in five normal men. Each subject received orally 5 mg of bromocriptine (Brc) daily for 8 weeks. Each received gonadotropin-releasing hormone (GnRH) stimulation tests at the beginning (control), and at 2, 4, 6, and 8 weeks after initiation of Brc treatment. We referred the basal plasma LH and a ratio of maximally GnRH-responded plasma LH to its basal level (R-Max) as indicators of secretory alterations of the LH. Mean basal levels of plasma LH in the five subjects at the beginning and those of R-Max were 3.4 +/- 2.3 (SD) mIU/mL and 8.5 +/- 2.9 units, respectively. Statistically, both the mean values of plasma LH and R-Max during the control period did not differ significantly from those obtained after Brc treatment, although mean basal levels of plasma prolactin during the control period (15.6 +/- 4.6 ng/mL) decreased significantly (p < 0.05) after initiation of treatment. A low dose of Brc administered to normal men for 8 weeks does not significantly influence pituitary secretion of LH.

Hypopituitarism

Basal tests Levels of LH/FSH may be suppressed by a raised prolactin level, and are therefore not interpretable unless prolactin is low or normal. In men, the combination of low LH and FSH in combination with a low testosterone confirms LH/FSH deficiency; a high testosterone would indicate a source elsewhere in the body (such as a testosterone-secreting tumor). In women, the diagnosis of LH/FSH deficiency depends on whether the woman has been through the menopause. Before the menopause, abnormal menstrual periods together with low estradiol and LH/FSH levels confirm a pituitary problem; after the menopause (when LH/FSH levels are normally elevated and the ovaries produce less estradiol), inappropriately low LH/FSH alone is sufficient. Stimulation tests with GnRH are possible, but their use is not encouraged.