Use Of Luteinizing Hormone-releasing Hormone Agonists Research Articles

Ovarian Function Suppression With Luteinizing Hormone-Releasing Hormone Agonists for the Treatment of Hormone Receptor-Positive Early Breast Cancer in Premenopausal Women.

Chemotherapy and endocrine therapies are mainstays of treatment for early and advanced hormone receptor-positive (HR+) breast cancer. In premenopausal women with HR+ tumors, the benefits of adding ovarian function suppression (OFS) to endocrine therapy have been debated. Consequently, for many years, tamoxifen monotherapy has been the standard of care for endocrine treatment in the adjuvant setting. Recent studies have, however, provided new evidence that, in some premenopausal patients, OFS in combination with tamoxifen or aromatase inhibitors (AIs) can significantly increase survival versus tamoxifen alone. Luteinizing hormone-releasing hormone agonists (LHRHa), including goserelin, triptorelin, and leuprorelin, achieve OFS through sustained suppression of the release of follicle-stimulating hormone and luteinizing hormone from the pituitary. In turn, this suppresses production and secretion of estradiol, an ovarian hormone that supports cancer cell growth, survival, and proliferation. In this review, we discuss the clinical evidence supporting the addition of LHRHa to adjuvant endocrine therapies, including tamoxifen and AIs, for premenopausal women with breast cancer. We also discuss the role of LHRHa use in combination with adjuvant chemotherapy to preserve ovarian function and fertility in young patients with breast cancer. Finally, we discuss important practical aspects of the use of LHRHa in breast cancer treatment, including side-effects, patient adherence to treatment, and the use of slow-release, long-acting drug formulations.

Adjuvant hormonal therapy and fertility preservation in premenopausal breast cancer: a survey among Italian oncologists.

Increasing age of first pregnancy among Italian women with premenopausal breast cancer makes adjuvant hormonal therapy a hot topic, justifying a survey on the therapeutic approach of Italian oncologists. From April to July 2012, an 11-item electronic questionnaire was submitted to Italian oncologists and 611 out of 974 invited filled questionnaires were collected from all over Italy. In total, 97.7% of patients aged <40 years needing only hormonal therapy would receive both tamoxifen and luteinizing hormone-releasing hormone agonists (LHRHa); 2.3% tamoxifen or LHRHa alone. For the majority of oncologists LHRHa was also the preferred choice to preserving fertility. Results are rather consistent with major guidelines but with a greater use of LHRHa and aromatase inhibitor.

LHRH agonists in prostate cancer: frequency of treatment, serum testosterone measurement and castrate level: consensus opinion from a roundtable discussion

ABSTRACTBackground: Options for lowering testosterone in patients with prostate cancer include bilateral orchiectomy, oestrogens and luteinising hormone-releasing hormone (LHRH) agonists. LHRH agonists have become widely used in the treatment of prostate cancer.Roundtable assembly: In May 2006, a team of experts convened a roundtable assembly to discuss key issues associated with the use of LHRH agonists in the treatment of prostate cancer.Roundtable discussion: The discussion centred on the frequency of treatment with LHRH agonists, the role of serum testosterone (ST) measurement as part of routine follow-up, and the recommended castrate level of ST. Several formulations of LHRH agonists are available, including 3-month depots that coincide with visit frequency for prostate-specific antigen (PSA) testing. Appropriate monitoring of patients receiving LHRH agonists continues to be based on PSA levels. ST determination is not recommended as part of routine follow-up, and does not provide additional prognostic benefit or improved overall management for the majority of patients. However, determination of ST may be useful in selected patients, such as those with rising PSA levels or in cases where there is doubt over LHRH agonist admin­istration or absorption. Achieving levels of ST similar to those obtained after orchiectomy is important for patient outcomes, although there is no evidence that a lower ST level (< 50 ng/dl) results in additional clinical benefits.Conclusions: LHRH agonists should be considered first-choice testosterone-lowering therapy for the treatment of prostate cancer, with the 3-month depot formulation providing optimal convenience and flexibility. Assessment of patients receiving LHRH agonists should be based on PSA levels rather than ST levels, although levels of ST similar to those obtained after orchiectomy still need to be achieved. Further studies are warranted before the potential therapeutic benefit of considerably lowered ST levels can be fully assessed.

Eligard ®: Pharmacokinetics, Effect on Testosterone and PSA Levels and Tolerability

Luteinising hormone releasing hormone (LHRH) agonists (e.g. leuprolide) have been the mainstay of advanced and metastatic prostate cancer treatment. LHRH agonist treatment has also become part of the treatment of early prostate cancer as neoadjuvant and adjuvant treatment to radical therapy. Early therapies consisted of daily injections of synthetic LHRH analogues (e.g. leuprolide, goserelin), but recent years have seen the development of depot formulations with 1, 3 or 4-monthly injections. These depot formulations have contributed considerably to the current widespread use of LHRH agonists, and have improved the patients’ adherence to treatment. Unfortunately, with these formulations the achievement of optimal control of testosterone defined as appropriate castration levels and low levels of breakthroughs, as well as acute-on-chronic responses, is currently overestimated. In order to achieve the optimal control of testosterone, a new depot formulation of leuprolide, Eligard ®, has been developed, which contains a novel delivery system (Atrigel ®) with potential advantages over the older systems. Eligard ® allows for a favourable pharmacokinetic profile, delivering a twofold higher quantity of LHRH agonist than seen with other available depot preparations in the European Union (EU), in a consistent and stable manner. As a result, testosterone levels are better suppressed and, unlike other delivery systems, Eligard ® achieves levels of testosterone as seen with orchiectomy and has, to date, shown no escape responses. In addition, clinical trials have shown that Eligard ® produces mild episodes of hot flushes. Eligard ® has a small volume which is administered subcutaneously with a very short needle, reducing injection site discomfort. Main adverse events associated with subcutaneous injection are mild and of short duration, comprising irritation, skin discolouration and erythema. It is concluded that Eligard ®, consisting of a novel delivery system with an improved pharmacokinetic profile compared with other existing depot formulations, leads to reliable and sustained testosterone suppression with a favourable side effect profile.

Role of Luteinising Hormone Releasing Hormone (LHRH) Agonists and Hormonal Treatment in the Management of Prostate Cancer

The use of luteinising hormone releasing hormone (LHRH) agonists has increasingly evolved during the past 10 years. This review paper aims to discuss the role of LHRH agonists in patients with prostate cancer, a leading cause of cancer death in men. To retrieve the most relevant randomised clinical trials (RCTs), a Medline search was performed in the last quarter of 2004. Only fully published studies in English language with at least 25 patients per treatment arm and those frequently cited in review articles were included in the current review. This review does not claim to have included every single study with the selected treatment options, but aimed at including the most important trials performed and fully published with these treatments. The retrieved studies are discussed and put into perspective of the EAU guidelines. Initially, LHRH agonists were part of the treatment strategy for patients with advanced or metastatic disease. Currently, LHRH agonists are increasingly used as a treatment option in a neoadjuvant and/or adjuvant setting for patients with early or localised disease. LHRH analogues are used as adjuvant hormonal therapy after radical prostatectomy, and as neoadjuvant and adjuvant treatment to radiotherapy. Patients with early or localised disease and a low Gleason score may experience clinical benefit from the neoadjuvant addition of LHRH agonists to radiotherapy. In patients with a high Gleason score and positive lymph nodes, adjuvant LHRH agonist treatment is considered standard therapy. In patients with rising prostate specific antigen (PSA) after radical treatment, hormonal therapy is often applied in an intermittent way, but results remain inconclusive. Maximum androgen blockade (MAB), a combination of a LHRH agonist and an antiandrogen, has been applied in advanced prostate cancer. However, due to the increased incidence of side effects and very modest survival benefits, there are few arguments to offer this treatment strategy to patients with prostate cancer. In summary, LHRH agonist therapy is important in the treatment of both early and advanced prostate cancer. Additional studies are needed to further define the optimal use of LHRH agonists within various patient risk groups.

Adjuvant hormone therapy after radiation or surgery for localized or locally advanced prostate cancer.

Prostate cancer is being diagnosed at an earlier age and earlier disease stage than previously and increasing numbers of relatively young men are receiving potentially curative radical prostatectomy or radiotherapy for early prostate cancer. Although many of these men have an excellent outcome, a significant proportion subsequently experience disease recurrence or cancer-related death. Men with unfavorable tumor characteristics at the time of radical prostatectomy or radiotherapy are particularly at high risk of experiencing disease recurrence. One strategy to improve outcome for these men is adjuvant hormone therapy (hormone therapy administered immediately after therapy of primary curative intent). Surgical castration (bilateral orchiectomy), medical castration using the luteinizing hormone-releasing hormone (LHRH) agonist goserelin, and antiandrogen monotherapy have been investigated as adjuvant hormone therapy to radical prostatectomy and radiotherapy, and each therapy has demonstrated clinical benefits because of a significant improvement in disease-free survival. Furthermore, data are available to indicate that adjuvant hormone therapy achieved by goserelin or bilateral orchiectomy improves overall survival, particularly in men at high risk of progression. Because the effects of LHRH agonists are reversible, they provide a more acceptable method of adjuvant therapy compared to bilateral orchiectomy, particularly in the adjuvant setting, and are preferred by patients. However, the adverse effects on quality of life, in particular on sexual interest and function and bone mineral density, may limit the use of LHRH agonists in some patients. However, these parameters are maintained with nonsteroidal antiandrogens. The first data from the Early Prostate Cancer program indicate that adjuvant bicalutamide 150 mg is associated with a significant improvement in progression-free survival after radical prostatectomy or radiotherapy. Gynecomastia and breast pain are the most common side effects associated with bicalutamide therapy. Medical or surgical castration in combination with an antiandrogen (combined androgen blockade) is another option for use as an adjuvant hormone therapy. However, no study has reported on the use of combined androgen blockade in this setting. Adjuvant hormone therapy provides clinicians with another treatment option for patients with early prostate cancer and unfavorable tumor characteristics.

Bone loss associated with the use of LHRH agonists in prostate cancer.

Hypogonadism is a recognised cause of osteoporosis in men. When patients with advanced prostate cancer are treated with luteinising hormone releasing hormone (LHRH) agonist analogues their circulating testosterone levels decline and these patients may develop fractures.We have undertaken a cross-sectional study on a cohort of patients treated with goserelin (n=41) and compared their bone density and bone turnover with patients with prostate cancer not on goserelin and elderly patients living in the community.There was no difference in bone density between the patients on treatment and those living in the community and there was a similar incidence of osteoporosis (50 and 42%, respectively). The bone marker measurements were higher in the treated patients: urine N-telopeptide (NTX) 80.1 (9) (mean (s.e.)) BCE/mmol, compared to 30.1 (2.9), P<0.001 in elderly patients; and bone alkaline phosphatase 41.9 (6.1) u/l in treated patients and 20.7 (1.5) in untreated prostate cancer patients, P<0.002. Patients on treatment with radionuclide scan evidence of metastases did not have higher bone marker values than those with negative scans.As increased bone turnover and low bone density are associated with enhanced risk of osteoporotic fractures, we suggest that patients on LHRH agonist analogues should receive advice and possibly anti-bone resorptive treatment with bisphosphonates to prevent further bone loss and fractures.Prostate Cancer and Prostatic Diseases (2001) 4, 161-166.

Luteinizing hormone-releasing hormone agonists for ovarian stimulation in assisted reproduction

Although the use of luteinizing hormone-releasing hormone (LHRH) agonists and human menopausal gonadotropin (hMG) for ovarian stimulation in assisted reproduction has gained widespread popularity, a number of major issues regarding their use remain unresolved. Some of these issues are examined in the light of recent developments. The routine use of LHRH agonists produces significantly higher pregnancy and livebirth rates compared with conventional methods of ovarian stimulation. A number of prospective, randomized studies have shown that the long protocol of LHRH agonist administration is superior to the short and ultrashort protocols, and it appears that early follicular phase initiation of the long protocol may be particularly beneficial. Another major advantage of the long protocol of LHRH agonist administration is that, with its use, precise timing of human chorionic gonadotropin (hCG) administration is not important. It would, therefore, appear that the routine use of LHRH agonists has both medical as well as practical advantages.

Endocrinological basis of hot flushes.

Hot flushes are frequent among women during natural, surgical, or pharmacological menopause. The available data suggest the involvement of estrogens, progestins, catecholestrogens, catecholamines, dopamine, endorphins, prostaglandins, luteinizing hormone (LH) and luteinizing hormone-releasing hormone (LH-RH) in the pathogenesis of flushes. At present the estrogen withdrawal and pulsatile luteinizing hormone (LH) secretion theories are most commonly accepted for explaining the development of this symptom. The use of LH-RH agonists offers an opportunity to focus on the probable origin and region that regulate the events of this phenomena, since the administration of this drug is associated with hot flushes, in spite of low gonadotropins and normal estrogen levels. Current data may suggest that the origin of this neurovegetative symptom lies in the hypothalamus.

Luteinizing hormone-releasing hormone (LHRH) agonists for treatment of advanced prostatic carcinoma

The identification of the decapeptide luteinizing hormone-releasing hormone (LHRH) has led to the development of LHRH agonists, which are a new class of drugs for the treatment of advanced prostate cancer. These peptides have a modified amino acid structure that makes them more potent than LHRH. Prolonged administration of LHRH agonists results in down-regulation of the LHRH receptors in the pituitary and decreased secretion of luteinizing hormone. The result is decreased production of testosterone by Leydig cells, which is the basis for the use of LHRH agonists to treat prostate cancer. The effectiveness of LHRH agonists has been demonstrated in the United States in several randomized, controlled clinical trials. Daily administration of leuprolide produced equivalent results compared with diethylstilbestrol (DES). More recently, in two separate, randomized studies, the long-acting LHRH agonist Zoladex (ICI Pharma, Wilmington, Delaware) produced the same objective response rate as DES or bilateral orchiectomy. The equivalent response rates obtained with LHRH agonists indicate that these drugs can now be considered a reasonable treatment option for patients with metastatic prostatic cancer.

Simultaneous administration of pure antiandrogens, a combination necessary for the use of luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer.

Although castration levels of serum androgens are consistently achieved after 2-3 weeks of treatment with luteinizing hormone-releasing hormone (LHRH) agonists, the administration of these peptides alone in adult men is always accompanied by a transient increase in plasma testosterone and dihydrotestosterone levels, which lasts for 5-15 days at the beginning of treatment and is accompanied by disease flare-up in some cases, thus seriously limiting the acceptability of this otherwise efficient and well-tolerated treatment. The present data show that the simultaneous administration of a pure antiandrogen neutralizes the influence of the transient increase in serum androgens on prostate cancer, as indicated by the 60% decrease in serum prostatic acid phosphatase observed within 5 days of combined treatment with an LHRH agonist and a pure antiandrogen. The addition of a pure antiandrogen thus makes fully acceptable the use of LHRH agonists as an advantageous substitute for surgical castration and estrogens in the treatment of prostate cancer.