GnRH Analogue Therapy Research Articles

Clinical review 60: Effects of gonadotropin-releasing hormone analog therapy on adult stature in precocious puberty

Clinical review 60: Effects of gonadotropin-releasing hormone analog therapy on adult stature in precocious puberty

Clinical review 60: Effects of gonadotropin-releasing hormone analog therapy on adult stature in precocious puberty.

Clinical review 60: Effects of gonadotropin-releasing hormone analog therapy on adult stature in precocious puberty.

A risk benefit assessment of drugs used in the treatment of endometriosis.

Medical treatments of endometriosis rely upon the hormonal dependence of endometriotic implants for further growth and extension. The cyclic nature of the symptoms means they may be helped by agents that suppress menstruation both from the endometrium and within the endometriotic lesions. In comparative trials, progestogens have been shown to achieve a similar reduction in symptoms and to induce regression of deposits, but to date there are few long term follow-up data concerning gestrinone. The recent introduction of gonadotrophin-releasing hormone (GnRH) agonists, highly effective at inducing a state of sustained hypoestrogenaemia, is providing another group of compounds suitable for use in the treatment of endometriosis. In comparative trials with danazol, a number of these compounds administered in novel formulations (as intranasal sprays or sustained release depots), have been shown to significantly reduce symptoms both during treatment and for 6 to 12 months post-treatment when compared with baseline. In addition, there are highly significant reductions in revised American Fertility Society (R-AFS) total and implant alone scores following 6 months' therapy. Whilst these changes are not significantly different from danazol, there are fewer patients discontinuing treatment with GnRH agonists than with danazol. The low circulating levels of 17 beta-estradiol seen during GnRH analogue therapy result in alterations of bone mineral metabolism similar to those observed at the menopause. Continued prolonged use would thus result in reduced bone mass and this factor will limit the duration of use of GnRH agonists long term until appropriate combination ('add-back') regimens to protect bone are developed.

Effects of long-term treatment with the gonadotropin-releasing hormone analog nafarelin in patients with non-functioning pituitary adenomas

The supposed origin of non-functioning pituitary adenomas (NFPA) from gonadotrophs prompted us to investigate the effects of the gonadotropin-releasing hormone (GnRH) analog nafarelin on hormonal and tumoral parameters in eight patients with NFPA, previously unsuccessfully operated and all hypogonadal. Nafarelin was administered intranasally for 1 year to all patients. Four patients received a dose of 1200 micrograms/day; the remaining four received 800 micrograms/day for 3 months, which was subsequently increased to 1200 micrograms/day. Basal gonadotrophin and alpha-subunit (alpha SU) levels were low-normal. In four patients (nos. 1,2,3,5) nafarelin significantly lowered luteinizing hormone (LH) levels, and also follicle-stimulating hormone (FSH) in three of them (nos. 1,2,3). Persistent FSH stimulation occurred in three patients (nos. 6,7,8), with a transient slight LH increase only in patient no. 8. In one patient (no. 7), alpha SU levels were persistently stimulated. Hormonal responses to an acute GnRH test during nafarelin administration were generally blunted when compared to the pretreatment responses. Immunofluorescence results, obtained before treatment in five adenomas (nos. 2,3,4,6,7), hae been as follows: positive for FSH-beta in all; negative for LH-beta in all, except a few positive cells in case no. 4; positive for alpha SU in three (nos. 2,3,7). No changes of visual field and tumor size occurred in any patient during treatment. However, one patient who showed a persistent increase in FSH levels exhibited left palpebral ptosis after 12 months of therapy and underwent a second transsphenoidal surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

GnRH agonist analogs and hysteroscopic resection of myomas

OBJECTIVES: The purpose of this study was to evaluate the effects of pretreatment with GnRH analogs and hysteroscopic resection of submucous myomas previously deemed to be contraindicated for this approach. METHODS: Twenty-five patients were included in this study. Patients were assessed by ultrasonography and diagnostic hysteroscopy. They were treated with depot GnRH analogs for 3 months and then scheduled for hysteroscopic surgery. RESULTS: After GnRH therapy the diameter was 61 ± 10% of the initial diameter. In one patient, therapy was almost ineffective. Hysteroscopic surgery was possible in all 25 patients. Seven patients presented an intramural myoma that was not possible to remove entirely during the first attempt. After dessication and 2 supplementary months of GnRH analog therapy, a second surgical attempt was successful in complete removal of the tumor in all except one case. In one patient hysterectomy 15 days after hysteroscopic surgery was necessary for incoercible bleeding due to a deep adenomiosis. CONCLUSIONS: A combined medical and surgical approach seems to reduce the limit of hysteroscopic surgery and avoid open myomectomy or hysterectomy in a well selected group of patients.

Gonadotropin-Releasing Hormone Agonists in the Treatment of Girls with Central Precocious Puberty

The onset of puberty before the age of 8 years in a girl is considered precocious. A child who presents with premature sexual development requires a thorough history, physical examination, and appropriate laboratory evaluation. Making the correct diagnosis is crucial to the selection of the appropriate form of therapy and management. Generally, CPP is the result of premature activation of the hypothalamic-pituitary-gonadal axis and can be successfully managed with long-acting GnRH agonists. In addition, GnRH analogue therapy has been shown to be safe, effective, and reversible. Treatment has resulted in a delay in the progression of secondary sexual development, normalization of the growth velocity, slowing of the rate of bone maturation, and an increase in the predicted final adult height. The GnRH agonists are ineffective in the therapy of gonadotropin-independent precocious puberty.

MR detection of degenerating uterine leiomyomas.

Gonadotropin-releasing hormone (GnRH) analogues have been advocated for the conservative management of uterine leiomyoma. These drugs induce a hypoestrogenic state and affect undegenerated myoma cells. Therefore, we evaluated the usefulness of MRI for distinguishing undegenerated and degenerated leiomyomas. Twenty lesions were studied in 16 patients with surgically resected leiomyoma. A 1.5 T unit was used to obtain T1- and T2-weighted images and Gd-DTPA-enhanced T1-weighted images. Signal intensity maps were made for each pulse sequence, and detailed histological maps were also made in the same plane as the MR images. Then the MR maps were compared with the histological maps of the resected specimens. Interstitial edema, the initial sign of degeneration, was detected as a high signal intensity region on T2-weighted images and showed enhancement with Gd-DTPA. Hyaline degeneration could not be distinguished from smooth muscle whorls on T1- and T2-weighted images. However, undegenerated leiomyoma could be distinguished from hyaline degeneration, because the former was slightly enhanced by Gd-DTPA but the latter was not. These findings showed that Gd-DTPA-enhanced MRI can distinguish undegenerated leiomyomas from degenerated leiomyomas and suggest that MRI may be useful for predicting the response of this tumor to GnRH analogue therapy.

Gonadotropin-Releasing Hormone Analogues in the Treatment of Sickle Cell Anemia-Associated Priapism

Priapism secondary to sickle cell anemia has been treated with a variety of therapeutic regimens. Recurrent sickle cell priapism is common and in many cases results when detumescence has not been achieved reliably. We report on a patient with sickle cell disease and recurrent priapism who was treated successfully for more than a year with monthly gonadotropin-releasing hormone analogue therapy after failure of standard medical management.

Long-term effectiveness of depot gonadotropin-releasing hormone analogue in the treatment of children with central precocious puberty.

To assess the efficacy and safety of a long-acting gonadotropin-releasing hormone analogue (GnRHa), leuprolide acetate for depot suspension (Lupron Depot), in the treatment of central precocious puberty in children, and to determine the reversibility of GnRHa therapy after it has been discontinued. Children with documented central precocious puberty were treated with Lupron Depot for 1.6 to 3.5 years. Their course of pubertal development, growth rate, skeletal maturation, and response to gonadorelin hydrochloride testing were compared before and during treatment. For those girls who finished treatment, an assessment of the reversibility of the GnRHa was performed by documenting a return to pubertal responses to gonadorelin testing, and by documenting menarche at an appropriately mature bone age. Community teaching hospital. Ten girls with central precocious puberty defined as pubertal maturation statistically advanced for age combined with a pubertal gonadotropin response to gonadorelin testing. Children who had been treated for less than 1.5 years were excluded, as were those with congenital adrenal hyperplasia. Patients who finished treatment have been followed up for up to 5 years, and will continue in follow-up throughout their reproductive life. SELECTION SAMPLE: A consecutive group of children with documented central precocious puberty was studied. Lupron Depot was administered as a single monthly subcutaneous injection to each patient. Treatment was usually discontinued by 10 to 11 years of age, at which time pubertal progression was allowed to resume. Mean peak serum concentrations of follicle-stimulating and luteinizing hormone responses to gonadorelin testing decreased significantly after the initial dose (from 21.8 +/- 4.5 [+/- SEM] to 2.4 +/- 0.2 IU/L for follicle-stimulating hormone and from 50.1 +/- 11.2 to 5.0 +/- 0.8 IU/L for luteinizing hormone) and remained suppressed for the duration of treatment. The progression of puberty slowed or reversed in all patients. Mean growth rate for chronologic age was significantly increased initially by 3.9 SDs and decreased to 0.9 SDs during treatment. The mean rates of skeletal maturation divided by the change in chronologic and height age changes over time were advanced (1.4 +/- 0.1 and 1.1 +/- 0.15, respectively) at the onset of therapy and decreased significantly to 0.7 +/- 0.1 and 0.8 +/- 0.1, respectively, on treatment. There was an increase in mean predicted height of 3.4 cm for all patients, and this was statistically significant. Thus, treatment with Lupron Depot at least maintained the predicted height at the onset of therapy. Girls who completed their course of treatment had pubertal gonadotropin responses to gonadorelin testing within 2 to 6 months, and menarche within the first year if skeletal maturation reached 13.0 to 13.5 years. No significant side effects of therapy were noted. Treatment of central precocious puberty in children using Lupron Depot is safe and efficacious. Its effects are readily reversible after treatment is discontinued, and menarche occurs at a normal bone age. Measurement of serum luteinizing hormone concentrations using an assay that is specific for the beta-subunit is necessary to monitor chemical suppression of luteinizing hormone during treatment. Longer-term studies, including reproductive history, will be needed before the potential effects of treatment on fertility can be assessed.

Serum concentrations of type I and III procollagen propeptides in healthy children and girls with central precocious puberty during treatment with gonadotropin-releasing hormone analog and cyproterone acetate.

Serum levels of type I and III procollagen propeptides (s-PICP and s-PIIINP) were measured in 466 healthy school children and in 23 girls with central precocious puberty (CPP) during GnRH analog and cyproterone acetate therapy, using two commercially available RIAs. In normal children, s-PICP and s-PIIINP changed significantly with age and pubertal development stages. For s-PIIINP, a peak was seen at 12 yr for girls and 13 yr for boys; no peak could be discerned for s-PICP. The prepubertal (Tanner stage 1) s-PICP value (mean +/- SD) for girls was 374 +/- 132 micrograms/L, the midpubertal value (stage 3) was 442 +/- 135 micrograms/L, and the postpubertal value (stage 5) was 203 +/- 103 micrograms/L. The mean s-PIIINP levels for girls were 9.1 +/- 2.4, 15.0 +/- 4.3, and 6.8 +/- 3.1 micrograms/L, respectively. For boys, levels were 362 +/- 119, 544 +/- 138, and 359 +/- 256 micrograms/L for s-PICP and 8.5 +/- 2.2, 14.5 +/- 5.0, and 8.6 +/- 3.8 micrograms/L for s-PIIINP (P < 0.001 for both propeptides in both boys and girls). There was, however, a large variation in normal values for both propeptides within the age groups and pubertal stages. There was a significant correlation of s-PICP and s-PIIINP levels to height velocity in girls (r = 0.35; P < 0.001 and r = 0.33; P < 0.001, respectively), while in boys, only s-PIIINP showed significant correlation to height velocity (r = 0.40; P < 0.001). In untreated girls with CPP, serum levels of s-PIIINP were elevated [PIIINP SD score (SDS), 2.13]. Levels of s-PICP were normal (PICP SDS, 0.39). Levels of both propeptides decreased within 2 months after initiation of therapy and remained below initial values (P < 0.01). The decrease in s-PIIINP after 2 months of therapy showed a significant correlation with the fall in height velocity SDS for chronological age after 6 months of therapy (r = 0.64; P < 0.01). We conclude that s-PIIINP and, to a lesser degree, s-PICP reflect growth in normal children, but due to the large variation, both propeptides seem unsuitable as markers for screening of growth disorders in children.

Endometrial resection after GnRH analogue therapy — a possible new treatment for fibromyomata

Endometrial resection after GnRH analogue therapy — a possible new treatment for fibromyomata

Gonadotropin Releasing Hormone Analogue and Growth Hormone Therapy in Precocious and Premature Puberty following Cranial Irradiation for Acute Lymphoblastic Leukaemia

Ten girls with early puberty secondary to cranial irradiation as a part of the treatment for acute lymphoblastic leukaemia (ALL) were treated with either gonadotropin-releasing hormone analogue (GnRHa) and human growth hormone (GH) (8 girls) or with GnRHa alone (2 girls). After 4 years of treatment, height SDS for bone age was improved in the group who received combined treatment (from -0.97 to +0.07, p < 0.001), in contrast to the 2 patients who received GnRHa alone in whom height standard deviation scores for bone age decreased (from -1.10 to -1.33). Sitting height in all patients was relatively shorter than leg length, and there was no significant alteration during the 4 years of treatment.

Predictive factors for the effect of gonadotrophin releasing hormone analogue therapy on the height of girls with idiopathic central precocious puberty

The factors influencing the final height of central precocious puberty patients treated with gonadotrophin releasing hormone (GnRH) analogues remain a critical issue. This study compares the predicted final height before and after GnRH analogue therapy to identify predictive factors for final height. Fourteen girls with idiopathic central precocious puberty were treated with a GnRH analogue. All had an active non-regressive form before therapy, full and permanent suppression of oestrogenic activity during therapy (duration greater than 2 years, 3.1 +/- 0.3 years, mean +/- SEM), and the pubertal pituitary-ovarian axis had normalized in all of them 1 year after the cessation of therapy. The mean predicted final height increased from 152 +/- 1.8 cm before therapy to 162.2 +/- 1.2 cm (P less than 0.01) at the last evaluation performed 4.5 +/- 0.3 years after the onset of therapy. The mean gain in predicted final height between the onset of therapy and the last evaluation was 10.2 +/- 1.1 cm. It was correlated with the following data recorded at the onset of therapy: bone age advance over chronological age (r = 0.66, P less than 0.02), predicted final height at the onset of therapy (r = -0.76, P less than 0.001), and the difference between the target height and the predicted height at onset of therapy (r = 0.76, P less than 0.001). We conclude that GnRH analogue therapy is more likely to improve final height prognosis in girls who initially present with a markedly advanced bone age and a great difference between their target and predicted heights. Both these parameters reflect the severity of the disease at diagnosis.

The impact of long-term gonadotropin-releasing hormone analogue treatment on preclinical abortions in patients with severe endometriosis undergoing in vitro fertilization-embryo transfer

To examine the relationship between endometriosis and preclinical abortions and to evaluate the effect of gonadotropin-releasing hormone analogue (GnRH-a) therapy on these pregnancies. Of 67 women with severe endometriosis referred to us for in vitro fertilization-embryo transfer (IVF-ET), 32 underwent ovarian stimulation for oocyte retrieval with menotropins (protocol A), whereas the other 35 were admitted for the procedure after a 6-month period of hormonal suppression with a GnRH agonist (protocol B). The clinical impact of the preclinical and clinical pregnancies in both treatment protocols were evaluated on the basis of oocyte classification and embryo quality score. All patients were treated in our IVF Unit. Clinical pregnancy was used as our main outcome measure of success. A significantly higher number of preclinical pregnancies (P less than 0.0001) occurred in patients treated by protocol A. After GnRH-a treatment, the preclinical pregnancy rate declined significantly (P less than 0.0001), whereas the clinical pregnancy rate per cycle and per transfer rose significantly (P less than 0.0001 and P less than 0.0001, respectively). Furthermore, clinical pregnancies had a significantly better mean embryo quality score in comparison with preclinical pregnancies (P less than 0.0001). It is concluded that combining GnRH-a therapy before IVF-ET provides an improved treatment modality for preclinical abortions and infertility associated with severe endometriosis.

Uterine leiomyosarcoma with massive necrosis diagnosed during gonadotropin-releasing hormone analog therapy for presumed uterine fibroid

Recurrence of heavy vaginal bleeding and massive necrosis of a uterine leiomyosarcoma are reported in a 41-year-old female who was being treated with GnRH-a for a presumed uterine fibroid. The pathogenic mechanisms of such an event are reviewed and discussed in light of the available literature on the subject of GnRH-a and the treatment of uterine smooth muscle neoplasms.

Time-related effects of gonadotropin-releasing hormone analog treatment in experimentally induced endometriosis in the rat

The purpose of our study was to characterize the time-dependent effect of gonadotropin-releasing hormone analog (GnRH-a) therapy on endometriosis explant using the rat model. Endometriosis was induced in 60 mature female rats. One group of treated animals as well as controls were killed at 2, 4, 6 and 8 weeks of treatment at which time the explant was evaluated. Explant volume was significantly reduced in all treatment groups, an effect that was more significant in animals treated for greater than or equal to 4 weeks compared with those treated for only 2 weeks. We conclude that GnRH-a treatment caused gradual regression of endometrial explant that was effectively complete by 4 weeks of treatment. We further conclude that this experimental model may be useful in the evaluation of other modes of endometriosis therapy.

Relationship between gonadotrophin-releasing hormone analogue therapy and bone loss; a review

Reproduction, Fertility and Development is an international journal publishing original research , review and comment in the fields of reproduction and developmental biology in humans, domestic animals and wildlife

Gonadotrophin‐Releasing Hormone Analogues as Therapeutic Probes in Human Growth and Development: Evidence from Children with Central Precocious Puberty

Statural growth and skeletal development were assessed in 87 girls with idiopathic central precocious puberty (CPP) during gonadotrophin-releasing hormone analogue (GnRHa)-induced suppression of gonadarche. Before the start of therapy, mean chronological age (CA) was 6.3 years and mean bone age (BA) was 10.6 years. During up to 6 consecutive years of complete suppression of gonadal sex steroid secretion, the mean height velocity decreased from 10.8 cm/year to prepubertal rates. At each interval height velocity was found to be inversely and negatively correlated with BA such that girls with advanced BAs grew at rates well below prepubertal norms but appropriately for their degree of skeletal maturation. Skeletal maturation similarly slowed during prolonged GnRHa administration (delta BA/delta CA = 0.6 +/- 0.1 over 3 years, mean +/- SD, n = 66) and was also negatively correlated with the BA before the start of therapy. Predicted adult height increased progressively during therapy; however, when analysed as changes in height SDS(BA), the impact of treatment was variable and correlated positively with the initial degree of skeletal maturation. The effect of GnRHa therapy on growth in children with CPP requires long-term study and is best analysed by employing a developmental perspective.

Adverse neurological symptoms after gonadotropin-releasing hormone analog therapy for in vitro fertilization cycles

Adverse neurological symptoms after gonadotropin-releasing hormone analog therapy for in vitro fertilization cycles

Hypothalamic Hamartomas and Sexual Precocity

We describe four male patients with hypothalamic hamartomas associated with sexual precocity. Our assessment of their management suggests that resection using current microsurgical techniques is a valid treatment option if the patient has a normal pubertal endocrine makeup, if the hamartoma is pedunculated, and if the patient is young enough to require years of parenteral medical treatment. Such surgical treatment can be curative, and subsequent growth and development can be normal (patients 1 and 2). However, if the patient is near to pubertal age (patient 3) or if neurosurgical or gonadotropin releasing hormone analogue treatment is not available, the natural history (patient 4) suggests that the only undesirable effects are accelerated growth, tall stature for age, and premature sexual development during childhood, as well as the psychosocial problems that may accompany them. Adult height may be compromised, although the two patients who did not undergo a surgical procedure and did not receive gonadotropin releasing hormone analogue therapy are above the lower limits of the normal range of adult male height. Therefore, if the hamartoma is pedunculated and cessation of pubertal development is desired, resection of the hamartoma is a reasonable therapeutic option.