Treatment Of Precocious Puberty Research Articles

Recent advances in the diagnosis and treatment of precocious puberty.

In the last two decades, the diagnosis and treatment of precocious puberty has undergone important changes. The use of supersensitive assays to determine gonadotropins and gonadal hormones has increased the sensitivity and decreased the number of blood samples required to assess the diagnosis. The introduction of gonadotropin-releasing hormone (GnRH) agonists produced a revolution in the diagnosis and treatment of this disorder. Recently, the use of long acting GnRH agonists improved the adherence of patients to medical treatment and decreased the need for uncomfortable repeated doses. The medications in the treatment of the GnRH independent causes of precocious puberty, and the important revelations in the pathophysiology of these disorders, have advanced our knowledge and management of the affected children.

Experience with cyproterone acetate in the treatment of precocious puberty.

The authors review their experience (1967-present) in the use of cyproterone acetate (CPA) in precocious puberty. CPA was found effective in persistently suppressing pituitary gonadotropic secretion when administered orally at a dose of 50 mg b.i.d. (70-100 mg/d). After the introduction of gonadotropic analogues (GnRHa) for treatment of central precocious puberty, short term use of CPA was found useful to counteract the initial stimulatory effect of the GnRHa as well as an adjunct drug in case of very active adrenarche causing advanced bone age during GnRHa treatment. The final heights of girls treated with CPA and girls treated with D-Trp6-LHRH were found comparable: 157.8+/-5.1 cm vs 159.6+/-6.3 cm, respectively. The main adverse effects were occasional fatigue due to partial adrenal insufficiency with CPA and gynecomastia in a few boys. Liver function tests were normal in all patients with the exception of one boy with severe hypothalamic disease, including precocious puberty, who developed liver cirrhosis 3 years after stopping CPA following 5 years treatment. Other indications for CPA treatment during childhood and adolescence, such as fast puberty, congenital adrenal hyperplasia and acne, are also mentioned.

Pharmacokinetics and pharmacodynamics of GnRH agonists: clinical implications in pediatrics.

Since 1981, GnRH agonist administration has been the treatment of choice for central precocious puberty. Continuous administration of the agonist, instead of permanently stimulating gonadotropin secretion, deeply suppresses LH and FSH levels and induces a marked inhibition of gonadal activity and regression of clinical symptoms. This inhibitory effect is due both to specific kinetic parameters relative to natural GnRH, and to marked alterations of the biosynthetic pathways of gonadotropin subunits. The half disappearance time of infused agonists is 3-10 fold that of natural GnRH. This means that the residence time of GnRH agonists is significantly longer than that of GnRH. The resistance of agonist to enzymatic degradation, mainly due to the substitution of a hydrophobic D-amino acid for glycine 6, is one of the factors involved in the increased availability of GnRH superagonists. The paradoxical effects of GnRH superagonists are still incompletely understood. In children long-term treated with depot formulations of triptorelin or leuprorelin, alpha-subunit secretion is markedly increased, and remains sensitive to exogenous GnRH, which demonstrates that the gonadotrophs are not totally desensitized. Despite the sustained stimulation of a-subunit secretion, no deleterious side effects, either during therapy or during post-therapy follow-up, have been reported in children treated with GnRH agonists. It should be noted that alpha-subunit responsiveness to exogenous GnRH decreases progressively after several years of treatment, although it is never completely abolished. On the other hand, LH beta-subunit secretion is suppressed as evidenced by radioimmunoassay of LH beta-subunit in serum chromatographic fractions from children treated with triptorelin. This differential pattern of secretion parallels that of mRNA levels in rat pituitary after in vivo exposure to triptorelin. Both pharmacodynamic and pharmacokinetic data can help diagnose the situations of resistance or escape. The lack of clinical effect of GnRH in the treatment of precocious puberty can be due to true resistance, or to an inappropriate injection schedule, or to abnormal metabolism. Measurement of serum alpha-subunit level, and, if needed, of serum agonist level, generally provides the answer.

Central Precocious Puberty in a Girl with McCune-Albright Syndrome Responds to Treatment with GnRH Analogue

GnRH analogues have been used with variable success for the treatment of precocious puberty in children with McCune-Albright syndrome (MAS). In general, children with a bone age of less than 13.5 yr have been reported not to have benefitted from GnRH therapy. In contrast, we have successfully treated a young girl with MAS and--probably secondary--central precocious puberty using Decapeptyl, a long acting GnRH analogue. The girl with MAS presented at the age of six years with café au lait spots, osseous lesions and precocious puberty. At initial presentation height was 130.7 cm (> 97 percentile), weight 27.5 kg (> 97 percentile), Tanner stage B3, PH3. Bone age was 11 yr. Magnetic resonance imaging of the brain was normal. Endocrine function tests were normal with the exception of biochemical evidence of central precocious puberty: LHRH test: LH 0.9/20.3, FSH 4.3/12.7 (mU/ml), E2 15.6 pg/ml. Therapy was started with 3.75 mg GnRH analogue i.m. every four weeks and was intensified two years after the beginning of therapy to 3.75 mg i.m. every three weeks. Three years after the start of treatment bone age was 12 yr and growth velocity was 2.5 cm/year. Tanner stage was B3, PH3 and LHRH testing revealed biochemical evidence for suppression of gonadotropins: LH < 0.5/1.0, FSH 1.9/2.5 (mU/ml). We hypothesize that a subgroup of patients with MAS might present with a central form of precocious puberty. This may be particularly so in children with a bone age greater than or equal to 11 yr. Central precocious puberty in these children might follow extensive sex steroid exposure due to the peripheral precocious puberty induced by the activating mutation of the Gs protein gene. This central form of precocious puberty responds to therapy with GnRH analogues.

Follow-Up Study of Children with Precocious Puberty Treated with Cyproterone Acetate

A total of 1840 children and adolescents treated with cyproterone acetate (CPA) to block gonadal function, as a treatment for precocious puberty, short stature and other disorders, were registered to survey for the risk of developing hepatic tumors. Patients responding to follow-up numbered 1552 (85%). The cumulative dose and duration of CPA therapy for boys and girls were 110.4g and 2.6 years, and 122.9 g and 2.8 years, respectively. Among the 1552 patients, five hepatoma cases were found. Four underwent successful surgery and remain alive and well to date. Two of the 5 cases had been given more than 500g, the other 3 more than 1000 g, of CPA. Three had also been given androgens before CPA administration. Although further follow-up is necessary to monitor for the development of adenoma and hepatoma, the risk of developing these tumors among patients to whom limited doses of CPA were administered appears to be negligible.

Tumor Size Reduction by Luteinizing Hormone-Releasing Hormone Analog Treatment for Precocious Puberty with Hypothalamic Hamartoma

Tumor Size Reduction by Luteinizing Hormone-Releasing Hormone Analog Treatment for Precocious Puberty with Hypothalamic Hamartoma

Use of Combined Gn-RH Agonist and hGH Therapy for Better Attaining the Goals in Precocious Puberty Treatment

We studied 30 girls (age 6.36 +/- 1.21 years, range 4.6-8.8) affected by idiopathic precocious puberty with significant reduction of height velocity (below the 25th centile) at the end of 1 year of Gn-RHa (triptorelin intramuscular depot) treatment, to evaluate GH-IGF-I axis activity and the effects of combined Gn-RHa plus hGH therapy. After 12 months, 15 patients continued Gn-RHa and started hGH therapy for 12 months, while 15 continued treatment with Gn-RHa alone (control group). We evaluated height velocity, bone age, urinary GH, serum IGF-I and IGFBP-3 levels throughout the study; plasma GHBP levels were determined only in the first 12 months of Gn-RHa treatment. Height velocity decreased significantly during Gn-RHa treatment; it increased significantly and became higher than the control group after 12 months of Gn-RHa plus hGH treatment. During Gn-RHa therapy alone, bone age progressed less than chronological age, while in the 12 months of Gn-RHa plus hGH treatment there was a slight nonsignificant increase in bone age progression in comparison to controls. Serum IGF-I and IGFBP-3 levels decreased significantly at 12 months of Gn-RHa therapy and increased significantly after Gn-RHa plus hGH treatment. Urinary GH levels showed the same behavior. Plasma GH binding to peak II-BP, slightly lower than the prepubertal normal range before treatment, significantly increased after 12 months of Gn-RHa treatment. Therefore, in these girls, during Gn-RHa treatment alone, we have a reduction in GH-IGF-I axis activity. During Gn-RHa plus hGH therapy there was a significant increase in height velocity, in urinary GH levels, in serum IGF-I and IGFBP-3 levels. Bone age did not seem to advance faster than chronological age and this may imply a better prediction in adult height. In our opinion, only in a small percentage of patients affected by precocious puberty (with a very low predicted adult height or an important reduction of growth velocity during Gn-RHa treatment) may an association with hGH therapy be useful.

DETERMINATION OF 24 HOUR URINARY ESTROGENS DURING PUBERTY

The first sign of puberty in girls can be observed by either clinical examination or the LH and FSH response to GnRH. However, serum estradiol levels can not be detected. The aim of the study was to develop a method for determine the early increase in estrogens and therefor we focused our work on.metabolites in the urine. 24h urine was collected from healthy girls with breast development of stage B1 or B2. The volume of urine was measured, albumin added (0.1% final concentration) in the samples for analysis. Sorbent solid extraction technology was used for extraction of the steroids. BondElut extraction cartridges C18 1211-3027 were used. The estrogen content was determined with bioMeriux Estradiol enzymatic U kit (nr 6.1483), using β-glucuronidase G7771 from sigma for hydrolyzing estrogens from glucuroconjugates. Total urinary estrogens (estradiol and estrone) varied between 0.01-0.04 μg per 24h for girls in Tanner stage B1 (n=3) and between 0.23-3.45 μg per 24h for girls in Tanner stage B2 (n=4). Determination of urinary estrogens seems to be a method to determine whether puberty has started or not. This could be used both in diagnosis and treatment of precocious puberty.

Two-year Results of Sustained-Release Leuprorelin Acetate (TAP-144-SR) Treatment in Children with Central Precocious Puberty

The effect of leuprolide acetate in depot suspension (TAP-144-SR), a synthetic analog of luteinizing hormone-relasing hormone, was studied in 34 patients with central precocious puberty. The doses were adjusted according to changes in hormone levels or clinical manifestations. The treatment was terminated or prematurely discontinued within 96 weeks in seven patients but was continued for more than 96 weeks in 27 patients.Mean basal and peak gonadotropin levels in response to LH-RH test decreased to the normal range from the fourth week of treatment and were maintained at prepubertal levels till 96 weeks. Mean concentrations of plasma testosterone and estradiol were mostly maintained at low levels during the treatment with TAP-144-SR.At 96 weeks of treatment, breast development had progressed in three, regressed in 10 and remained at the same stage in the other patients. The growth velocity was significantly suppressed from the pretreatment rate of 9.83 ±5.70 cm/year to 5.81 ± 2.80cm/year at 48 weeks of treatment (32 patients) and further to 4.87 ± 2.20 cm/year at 96 weeks (27 patients). The ratio δ bone age/ δchronological age for all the patients was 0.83 ± 0.78 at 48 weeks of treatment and 0.69 ± 0.47 at 96 weeks. The progression of bone age was suppressed by the treatment, especially in those patients with an initial bone age of 12 years or older.Of the adverse effects that appeared, those presumably related directly to TAP-144-SR were only genital bleeding in the stimulatory phase following the initial dose, and redness and induration at the site of injection. The once-monthly injection is a regimen well tolerated by children, and when its reliability and efficacy are considered, TAP-144-SR will be the drug of first choice in the treatment of precocious puberty.

Pathogenesis and therapy of precocious puberty

This review highlights recent reports on the diagnosis and treatment of precocious puberty. Diagnostic evaluation should include radiologic studies (particularly magnetic resonance imaging) to find a central nervous system-related cause, such as hypothalamic hamartoma, empty sella, or posttraumatic injury. Evaluation should also include laboratory tests for chorionic gonadotropin-secreting tumors (in boys), accurate measurement of pituitary gonad, and pelvic ultrasonography. Management of luteinizing hormone-releasing hormone (LHRH)-dependent precocious puberty with an LHRH agonist improves predicted adult height. Treatment is most convenient with monthly injections of a depot form of LHRH analogue. Although treatment with LHRH analogue usually reverses the puberty-induced increase in growth hormone secretion, growth hormone secretion usually remains appropriate for body mass index, and growth hormone treatment is not indicated.

10 Developments in the control of testicular function

Clinicians and clinical investigators have developed improved means for controlling testicular function in men. New and refined approaches for stimulation and inhibition of the hypothalamic-pituitary-testicular axis are now available. This chapter reviewed the most successful ways to inhibit the reproductive axis in men and its current application to the treatment of precocious puberty, metastatic prostate cancer, benign prostate hyperplasia and as prospective male contraceptives. Safe, effective and reversible medical approaches to male contraception are now approaching reality. Azoospermia and severe oligozoo/azoospermia can now be accomplished in the majority of men with combined GnRH antagonists and replacement doses of testosterone. Androgens and androgen-progestogen concentrations will induce azoospermia in over 90% of Asian men and azoospermia or severe oligospermia in Caucasian ethnic groups. Field trials are ongoing to determine whether testosterone administration will be more effective than condoms as contraceptives. True precocious puberty can now be managed more effectively than in the past by suppression of gonadotropin secretion with GnRH analogues. Precocious puberty due to other causes can be treated more effectively with inhibitors of steroidogenesis and blockers of androgen action. Metastatic prostate cancer, previously treatable with either castration or oestrogens, is now amenable to suppression of androgen secretion. GnRH analogues are given either alone or combined with blockers of androgen action. While significant palliative effects are observed with endocrine ablative therapy in most men with Stage C or D prostate cancer, modest increases in duration of survival may be seen. Benign prostate hyperplasia was previously approachable only with surgical intervention. Recent data have suggested that medical treatment with 5 alpha-reductase inhibitors and/or selective alpha-adrenergic blockers may offer non-surgical alternatives in some patients. More data are needed to determine the role of medical management of this common disorder.

Recent advances in the management of sexual precocity in girls

Sexual precocity has important psychosocial implications for the prematurely developing child, as well as being associated in some cases with significant pathology. Conscientious evaluation and initiation of effective therapy can have a significant impact on improving long-term outcome. The differentiation between complete sexual precocity with activation of the hypothalamic-pituitary axis and incomplete sexual precocity without activation of the central reproductive system is of paramount importance. In incomplete sexual precocity, the sex steroids are of exogenous, adrenal, or gonadal origin. Premature adrenarche presents with the early development of pubic hair only and must be distinguished from adrenal hyperplasia or an androgen-secreting neoplasm, which may be associated with accelerated growth, advanced bone age, and virilization. When incomplete sexual precocity involves the ovary, ovarian tumors must be considered. Other causes of incomplete sexual precocity include hypothyroidism and gonadotropin-independent precocity such as McCune-Albright syndrome. Complete sexual precocity or precocious puberty of central origin is diagnosed in girls by gonadotropin-releasing hormone challenge yielding a stimulated luteinizing hormone peak greater than 15 IU/L. Radiologic evaluation of the central axis is necessary. Treatment of precocious puberty relies on the use of potent agonists of gonadotropin-releasing hormone that reversibly suppress the prematurely activated pituitary. Depot preparations are efficacious. Early initiation and careful monitoring of treatment can reduce physical signs of development, improve the likelihood for normal adult height, and postpone normal pubertal progression to a more appropriate age.

Treatment of Precocious Puberty with Continuous Subcutaneous Infusion of Native Luteinizing Hormone Releasing Hormone

Treatment of Precocious Puberty with Continuous Subcutaneous Infusion of Native Luteinizing Hormone Releasing Hormone

Suppression of Gonadotropin Secretion by a Long-Acting Gonadotropin-Releasing Hormone Analog (Leuprolide Acetate, Lupron Depot) in Children with Precocious Puberty

The GnRH analog leuprolide acetate has been shown to be effective in the treatment of precocious puberty when given as a daily sc injection. We studied the effectiveness of a single im dose of a new depot form of leuprolide in suppressing estradiol and gonadotropin secretion in children with precocity. Five girls with previously untreated precocity showed significant decreases in basal serum estradiol and FSH levels and in peak LH levels (after GnRH testing) 30 days after a single im dose of leuprolide acetate for depot suspension. Mean peak FSH levels also fell greatly, but the difference was not significant. No adverse effects were noted during the first 4-6 months of monthly im injections. Depot im leuprolide appears to be effective in suppressing estradiol and gonadotropin secretion, and may be a useful method of treating children with central precocious puberty.

Treatment of precocious puberty using an intranasal luteinizing hormone‐releasing hormone analogue: Buserelin

Fourteen patients with precocious puberty were treated for 1-3 years with 900-1800 micrograms/day of intranasal (i.n.) Buserelin. The peak luteinizing hormone and follicle-stimulating hormone responses to intravenous luteinizing hormone-releasing hormone were reduced significantly 4 weeks after starting treatment and remained suppressed while the patients were on treatment. Two patients were withdrawn because of drug non-compliance. Three patients showed regression of pubertal changes, four patients showed no progression and five patients showed progression of breast size or pubic hair staging after 1.5-2 years of treatment. Treatment was changed to the subcutaneous route in two patients because of hormonal escape and accelerated skeletal maturation. The mean growth velocity decreased from 10.78 cm/year (s.e.m. = 0.64) to 7.06 cm/year (s.e.m. = 0.85) after 1 year of treatment (P less than 0.005). After an increase in dosage (from 900 micrograms/day to 1800 micrograms/day) in most patients, further significant falls in growth velocity to 5.29 cm/year (s.e.m. = 0.45), 4.63 cm/year (s.e.m. = 0.8) and 5.06 cm/year (s.e.m. = 0.5) were observed at 18, 24 and 30 months, respectively, compared with the pretreatment value (P less than 0.001). With treatment, the increased rate of skeletal maturation normalized. In 10 patients who had completed 2 years of treatment, the height standard deviation score for bone age improved from a pretreatment value of -2.42 +/- 0.42 to -1.6 +/- 0.42 after 2 years of treatment (P less than 0.01), indicating an improvement in height prognosis. It is concluded that i.n. Buserelin at a dose of 1800 micrograms/day is effective in the treatment of most but not all patients with precocious puberty.

GnRH agonists.

The development of GnRH agonists has had a major impact on the practice of gynecology and reproductive endocrinology. The clinical usefulness of GnRH agonists will increase as modes of administration are improved and indications become better defined. GnRH agonists and, potentially, antagonists will provide a prompt, effective, and reversible method of suppressing ovarian function. GnRH agonists may soon become a treatment of choice for many of the noncontraceptive uses of oral contraceptives. Current indications for GnRH agonist administration are best divided into two groups: short-term (less than 6 months) and long-term (greater than 6 months) suppression. Short-term administration of GnRH agonist include most of the current usage of GnRH agonists. Short-term administration avoids most of the side effects of GnRH agonist and offers the most potential for development of GnRH antagonists. Short-term therapy has been shown to be particularly effective in the preoperative treatment of fibroids, suppression of ovarian function before ovulation induction, for short-term suppression of endometriosis, and for diagnostic purposes to determine whether a medical illness is related to ovarian function. Chronic administration of GnRH agonist has produced varying degrees of success. The treatment of precocious puberty is probably the perfect indication for GnRH agonist suppression. The disease is completely reversed with a remarkable absence of side effects. Long-term administration for metastatic breast or prostatic cancer has been shown to be as efficacious as other forms of gonadal suppression and the potential benefits of suppression outweigh the potential side effects of long-term suppression. The risk-benefit ratio must be carefully analyzed for the other indications for long-term suppression. Long-term suppression could be used for medical illnesses exacerbated by the menstrual cycle, painful symptoms related to endometriosis, contraception, and suppression of hyperandrogynism. Although initial studies show the agonist to be quite effective in treating all of these disorders, long-term suppression also may result in potential serious side effects related to hypoestrogenism including hot flashes and osteoporosis. Long-term administration of GnRH agonist may become feasible by lowering the dose and degree of suppression or by combining GnRH agonist with estrogen or progestin replacement, or both.

DEPOT LEUPROLTDE ACETATE FOR TREATMENT OF PRECOCIOUS PUBERTY

Leuprolide acetate (D-Leu 6 des-Gly-NH2(10), Pro-ethylamide9) for depot suspension has been shown to be effective in suppressing gonadotropins in 6 patients. Serum LH and FSH response to exogenous LHRH was obliterated after 4 weeks and weekly urinary gonadotropin levels during depot therapy were suppressed. This form of this drug should be effective in the treatment of precocious puberty.

Effect of Cyproterone Acetate on Aromatase Activity in Cultured Human Genital Skin Fibroblasts

Cyproterone acetate(CA), a well-known competitive antiandrogen, has been used for the treatment of precocious puberty, prostatic adenocarcinoma, hirsutism and hypersexuality. However, there have been some reports of troublesome gynecomastia developing during the use of this drug. It was, therefore, of interest to investigate the effect of CA on peripheral aromatization, since it is the major source of circulating estrogens in men. Our recent studies of aromatase activity in human skin fibroblasts demonstrated that the skin is an important site of extraglandular aromatase activity in men and suggested that these cells might provide a valuable new system in which to study the enzyme. Estrogen formation was assayed by the [3H]H2O technique, after 3h incubation of the cells with androstenedione. The initial experiment was designed to test the effect of CA (10(-8) to 10(-5) M) on baseline aromatase activity during a 12h preincubation in the presence of fetal bovine serum (FBS). Baseline aromatase activity was not affected by the presence of CA, whereas medroxyprogesterone acetate, a similar synthetic progestogen, induced a 2-fold stimulation of aromatase activity at a concentration of 10(-5) M. In cells preincubated with dexamethasone (DEX) in the presence of FBS, aromatase activity was stimulated markedly. When the cells were preincubated in the medium containing FBS with DEX (2.5 X 10(-7) M) in the presence of CA (10(-7) to 10(-4) M), DEX-stimulated levels of aromatase activity were inhibited by CA in a dose-dependent fashion. A competitive binding assay using [3H]DEX, showed that CA was able to compete with DEX for glucocorticoid receptor and the relative binding affinity of CA was approximately 50 times less than DEX. This suggested that the inhibitory effect of CA was due to competition with DEX for receptor binding. Aromatase activity was also stimulated by (Bu)2cAMP (1mM) in the absence of FBS. The stimulatory effect of (Bu)2 cAMP was maximal after 12-24h of preincubation, and this level was maintained for 60h. Similar to the DEX stimulation, stimulation of aromatase activity by (Bu)2cAMP required both RNA and protein synthesis, since the stimulatory effect of (Bu)2cAMP was abolished by co-preincubation with cycloheximide or actinomycin D. When CA was present during either the 12h preincubation or assay incubation, no difference was found in the (Bu)2cAMP-stimulated levels of aromatase activity. On the other hand, the non-aromatizable androgen dihydrotestosterone (DHT) (10(-8) to 10(-6) M) inhibited the stimulation of aromatase activity by (Bu)2cAMP in a dose-dependent fashion.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical applications of gonadotrophin-releasing hormone and its analogues.

The clinical applications of GnRH and its analogues are discussed. GnRH can be used diagnostically to assess the releasable pool of LH and the status of gonadotrophin secretion. Clinically it can be used to induce follicle growth and ovulation in patients with hypogonadotrophic amenorrhoea, especially when given in pulsatile form, and there are reports that it might also stimulate spermatogenesis in men with hypogonadotrophic hypogonadism. Analogues are proving valuable in the treatment of precocious puberty, but are not yet practical for contraception. They are more valuable in the treatment of endometriosis, hormone-dependent cancers, the polycystic ovary and for the induction of ovulation for in-vitro fertilization.

Gonadotropin andα-Subunit Secretion During Long Term Pituitary Suppression byD-Trp6-Luteinizing Hormone-Releasing Hormone Microcapsules as Treatment of Precocious Puberty*

Short term treatment with GnRH agonists has been reported to increase plasma gonadotropin alpha-subunit (Gn alpha) levels while decreasing plasma immunoreactive LH (IR-LH) levels. In this study we examined the effect of D-Trp6-LHRH (LHRH-A) in microcapsules (60 micrograms/kg, im, every 28 days for 1 yr) in 13 girls suffering from precocious puberty. Plasma IR-Gn alpha was measured by RIA; plasma IR-LH and IR-FSH were measured by both polyclonal RIAs and monoclonal immunoradiometric assays (IRMA). Before treatment, basal IR-LH and IR-FSH levels and peak responses to LHRH measured by both RIA and IRMA were similar, and the Gn alpha response paralleled that of LH. After the first injection of LHRH-A, RIA LH levels were significantly higher than pretreatment levels until day 21, while IRMA LH levels transiently increased, but returned to pretreatment levels by day 7 and became lower thereafter (P less than 0.005). Plasma IR-Gn alpha levels increased from days 3-21 (P less than 0.05). After 1.5 months of treatment, basal RIA LH levels remained detectable and not different from pretreatment levels; IRMA LH levels were very low. The mean RIA and IRMA LH responses to LHRH were decreased at 1.5 and 12 months (P less than 0.01). Basal plasma RIA and IRMA FSH levels were similar during treatment (P greater than 0.05) and significantly lower than pretreatment values (P less than 0.01). The mean RIA and IRMA FSH responses to LHRH decreased significantly at 1.5 months (P less than 0.001). After 12 months, both RIA and IRMA FSH responses were increased, but IRMA values were significantly lower than RIA values. A sustained increase in basal Gn alpha values occurred, but there was a tendency for the peak levels after LHRH treatment to decrease, becoming significantly lower than pretreatment peak levels after 1 yr. The chromatographic analysis on Sephadex G-100 of a pool of plasma samples collected during a LHRH test in three children treated for 6 months indicated that IR-Gn alpha coeluted with [125I]Gn alpha. The large discrepancy between RIA and IRMA LH values suggests the secretion of unusual LH molecules which are recognized by RIA but not by IRMA. The sustained release of large amounts of IR-Gn alpha indicates dissociated effects of LHRH-A on alpha- and beta-subunit secretion by the gonadotrophs. The sustained response of Gn alpha to LHRH demonstrates that gonadotroph cell LHRH receptors are still responsive to LHRH during treatment with a LHRH agonist.