Elsevier

Peptides

Volume 20, Issue 10, October 1999, Pages 1247-1262
Peptides

Review Paper
Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis☆

☆ Presented as a plenary lecture at the 10th World Congress on Human Reproduction, May 5, 1999, Salvador, Bahia, Brazil.
https://doi.org/10.1016/S0196-9781(99)00130-8Get rights and content

Abstract

The development of the luteinizing hormone-releasing hormone (LH-RH) agonists and antagonists and the principles of their clinical use were reviewed. In the 28 years that have elapsed since the elucidation of the structure of LH-RH, various applications in gynecology, reproductive medicine, and oncology have been established for LH-RH agonists and antagonists. These clinical applications are based on inhibition of the pituitary and the gonads. The advantage of the LH-RH antagonists is due to the fact that they inhibit the secretion of gonadotropins and sex steroids immediately after the first injection and thus achieve rapid therapeutic effects in contrast to the agonists, which require repeated administration. LH-RH antagonists should find applications in the treatment of benign gynecologic disorders and benign prostatic hypertrophy and in assisted reproduction programs. The primary treatment of advanced androgen-dependent prostate cancer is presently based on the use of depot preparations of LH-RH agonists, but antagonists like Cetrorelix already have been tried successfully. Antagonists of LH-RH might be more efficacious than agonists in treatment of patients with breast cancer as well as ovarian and endometrial cancer. Recently, practical cytotoxic analogs of LH-RH that can be targeted to LH-RH receptors on tumors have been synthesized and successfully tested in experimental cancer models. Targeted cytotoxic LH-RH analogs show a great promise for therapy of prostate, breast, and ovarian cancers.

Introduction

More than 25 years have passed since my laboratory first isolated hypothalamic luteinizing hormone-releasing hormone (LH-RH), identified its structure, and synthesized it [4], [109], [110], [146], [147], [148], [153], [159]. After I announced the structure of porcine LH-RH (Fig. 1 ) at the Endocrine Society meeting in San Francisco in June 1971 [146], it was synthesized by Guillemin’s group [116]. The following year, they reported the amino acid sequence of ovine LH-RH [16], which proved to be the same as that of pig LH-RH. Subsequent studies showed that the structure of hypothalamic LH-RH in all mammalian species examined, including human, is identical. Mammalian LH-RH is also active in birds and in some species of fish, but at least 12 additional molecular forms of LH-RH that differ structurally have been identified in birds, reptiles, amphibians, fishes, other vertebrates, and protochordata [133]. Another isoform of decapeptide LH-RH—LH-RH-II—also has been reported in mammalian brain.

LH-RH is the primary link between the brain and the pituitary in the regulation of gonadal functions and plays a pivotal role in vertebrate reproduction. Because both natural LH-RH and the synthetic decapeptide corresponding to its structure possessed major follicle-stimulating hormone (FSH)-releasing as well as LH-releasing activity, we put forward a concept that one hypothalamic hormone, designated LH-RH/FSH-RH or simply gonadotropin-releasing hormone (Gn-RH) [148], controls the secretion of both gonadotropins from the pituitary gland. Although LH-RH is now accepted as the main FSH-releasing hormone, for reasons of historical continuity the abbreviation LH-RH was recommended for naming its analogs [154], [156]. In addition, the abbreviation Gn-RH for gonadotropin-releasing hormone is confusing because it is too similar to GH-RH (growth hormone-releasing hormone), for which many agonistic and antagonistic analogs already exist [156].

Even before synthetic LH-RH became available, we clearly demonstrated in clinical studies carried out in 1968 and 1969 in Mexico that highly purified porcine LH-RH, LH, and FSH release in men and women under a variety of conditions [81], [82], [153]. Subsequently, various clinicians, including our collaborators, carried out extensive clinical studies with synthetic LH-RH [154], [155]. LH-RH was utilized diagnostically to determine the pituitary LH and FSH reserve, as well as therapeutically for induction of ovulation in amenorrheic women and treatment of oligospermia and cryptorchidism [155]. At present, synthetic LH-RH is used mostly for evaluating hypothalamic-pituitary gonadotropin function and for induction of ovulation.

In 1971, we also postulated that replacement of one or more amino acids in LH-RH might result in analogs with increased LH-releasing activity or antagonistic action [152]. Since 1972, systematic work has been proceeding to synthesize agonistic and antagonistic analogs of LH-RH. A powerful interest in medical applications of LH-RH derivatives stimulated this undertaking. Thus, the intense activity that has occurred in this field was caused by the desire to synthesize superactive analogs with prolonged biologic activity that would be more useful therapeutically than LH-RH itself and to develop antagonistic analogs that were intended at first for contraception and subsequently for gynecological and oncological use [149], [155]. However, at that time, we could not imagine the impact and the variety of application, including major uses in oncology, that LH-RH analogs would turn out to have. In the past 25 years, more than 3000 analogs of LH-RH have been synthesized [5], [31], [32], [80], [139], [144], [149], [150], [151], [177]. Many agonistic analogs more potent than the parent hormone have been made [31], [80], [144], [149], [150], [155], [177]. Several of these analogs are being used clinically, and the list of their applications is steadily expanding. Potent antagonists of LH-RH such as Cetrorelix [5], [139], [150], [151] that are suitable for clinical use have also been synthesized. In the past few years, diverse cytotoxic analogs of LH-RH have been developed in our laboratory. These analogs consist of cytotoxic radicals, such as doxorubicin, linked to LH-RH agonists that function as carriers that can be targeted to LH-RH receptors on tumors [118]. In experimental studies, these analogs eradicated various tumors and their metastases. LH-RH antagonists and cytotoxic analogs appear to be important additions to clinical armamentarium.

Thus, the discovery of LH-RH has led to many practical clinical uses, and analogs of LH-RH have various important applications in gynecology and oncology. I will now review some selected experimental and clinical findings on the agonistic, antagonistic, and cytotoxic analogs of LH-RH. Various uses of LH-RH analogs in reproductive medicine have been covered recently by others and by me [145], so I will cite those topics only very briefly and will concentrate on applications of the agonists, antagonists, and cytotoxic analogs of LH-RH in cancer therapy.

The half-life of LH-RH is very short—about 2–4 min—and more potent and longer-acting analogs were considered to be necessary for clinical applications. The studies on the relationship between structure and biologic activity showed that histidine in position 2 and tryptophan in position 3 play a functional role in the biologic activity of LH-RH, and simple substitutions or deletions in this active center decrease or abolish LH-RH activity [31], [80], [155]. However, considerable activity can be obtained by the substitution of these amino acids by structures possessing similar acid-base and hydrogen-bonding capacity, or suitably oriented aromatic nuclei capable of generating similar electronic interactions. Positions 2 and 3 are also the preferred ones for substitution to generate inhibitory activity. However, the tripeptide pyro-Glu-His-Trp or its amide are inactive. Amino acids in positions 1 and 4–10 are essential for binding to the receptors and exerting conformational effects [31], [80], [155]. Substitutions in positions 6 and 10 can lead to superactive peptides. Thus, several LH-RH analogs substituted in positions 6, 10, or both are much more active than LH-RH and also possess prolonged activity [24], [31], [46], [80], [144], [149], [150], [177]. Of these, the most important are: [d-Trp6]LH-RH (Decapeptyl®, triptorelin) (Fig. 2), [d-Leu6,Pro9-NHET]LH-RH (Leuprolide, Lupron™), [d-Ser(But)6,Pro9-NHET]LH-RH (Buserelin), [d-Ser(But)6,Aza-Gly10]LH-RH (Zoladex™, goserelin), and [d-Nal(2)6]LH-RH (Nafarelin), which are 50–100 times more potent than LH-RH [24], [31], [46], [80], [144], [149], [150], [177].

This greater biologic activity of the analogs is due both to increased resistance to enzymatic degradation and an enhancement in receptor affinity. The substitution of Gly6 by d-amino acids renders the analog more resistant to degradation by endopeptidases, which cleave LH-RH at this position and which are widely distributed in mammalian tissues [80].

Although an acute injection of superactive agonists of LHRH induces a marked and sustained release of LH and FSH, paradoxically, chronic administration produces inhibitory effects [22], [31], [71], [80], [142], [144], [149], [150], [177]. This can be explained by the findings that LH-RH secretion is pulsatile and physiologic stimulation of secretion of gonadotropins requires intermittent LH-RH release [11], [89]. Continuous stimulation of the pituitary by chronic administration of LH-RH or its superactive agonists produces inhibition of hypophyseal-gonadal axis through the process of down-regulation (a reduction in the number) of pituitary receptors for LH-RH, decrease in expression of LH-RH receptor gene, desensitization of the pituitary gonadotrophs, and a suppression of circulating levels of LH and sex steroids [21], [39], [119], [144], [149], [150], [151]. The molecular and cellular basis of the LH-RH action on the pituitary and signal transduction pathways of LH-RH receptors have been reviewed expertly [21], [168]. The cloning of cDNA for mouse, rat, and human LH-RH receptor and the organization of LH-RH receptor gene have been reported [77], [167].

These processes that can be produced by repeated administration or depot preparations of LH-RH agonists have important clinical applications. Treatment of central precocious puberty, polycystic ovarian disease, hirsutism, and the use for in vitro fertilization and embryo-transfer programs are based on the suppression of gonadotrophin secretion (selective medical hypophysectomy). Therapy of sex hormone-dependent malignant neoplasms, typified by prostate and breast cancer, endometrial carcinoma, as well as of other diseases or conditions such as benign prostate hyperplasia, uterine leiomyomas, and endometriosis, is based on the reversible medical castration and the creation of a state of sex steroid deprivation.

LH-RH analogs also exert direct inhibitory effects on breast, prostate, ovarian, and endometrial cancers mediated through specific LH-RH receptors on the tumor cells [29], [34], [35], [36], [40], [100], [134], [150], [151], [167]. These effects are further discussed in the sections on specific neoplasms. The existence of functional regulatory LH-RH loops in prostate cancer and ovarian cancer also has been postulated [29], [34]. These systems would consist of locally produced LH-RH-like peptides and specific LH-RH receptors [29], [34], [35].

The design of modified structures that might compete with a biologically active compound for the same receptor sites, and yet exhibit little intrinsic activity, is a classic concept that has been used to develop a number of drugs, such as sulfanilamide and 5-fluorouracil. Since 1972, hundreds of LH-RH antagonists have been synthesized and assayed in animals [31], [32], [80], [144], [149], [150], [177]. Early inhibitory analogs were hydrophilic and contained replacements or deletions for His in position 2 and Trp in position 3 [80], [140], [149], [155]. Later, it was found that incorporation of a d-amino acid in position 6 increased the inhibitory activity [80], [155]. [d-Phe2,d-Trp3,d-Phe6]LH-RH was the first inhibitory analog found to be active in men and women [17], [52], [144], [149], [155]. Insertion of d-arginine in position 6 of LH-RH antagonists increased the inhibitory activity [80], [144], [149]. However, hydrophilic antagonists with d-Arg or related basic residues in position 6 induced histamine liberation resulting in transient edema and other anaphylactoid reactions [32], [80], [144], [149].

To eliminate the undesirable edematogenic effect, new analogs with neutral d-ureidoalkyl amino acids, such as d-Cit at position 6, were synthesized in our laboratory [5]. Among these antagonists devoid of any significant edematogenic effects, [Ac-d-Nal(2)1,d-Phe(4Cl)2,d-Pal(3)3,d-Cit6,d-Ala10]LH-RH (SB-75) (Cetrorelix; Fig. 3 ) had the highest overall inhibitory activity and receptor binding affinity [5], [139], [144], [150].

Other groups have also reported different structural modifications that preserve high activity and diminish anaphylactoid activity. Antagonists like antide [N-Ac-d-Nal(2)1,d-Phe(4Cl)2,d-Pal(3)3,Lys(Nic)5,d-Lys(Nic)6,Lys(iPr)8,d-Ala10]LH-RH [103] and Nal-Glu antagonist [Ac-d-Nal(2)1,d-Phe(4Cl)2,d-Pal(3)3,Arg5,d-Glu6(AA),d-Ala10]LH-RH [141] are potent, although antide has low solubility and Nal-Glu antagonist caused some clinical side effects. Among other antagonists that are being developed are Azaline B [Ac-d-Nal1,d-Phe(4Cl)2,d-Pal3,Aph5(Atz),Aph6(Atz),ILys8,d-Ala10]-GnRH [70], Ganirelix [N-Ac-d-Nal(2)1,d-p-Cl-Phe2,d-Pal(3)3,d-hArg(Et2)6,l-hArg(Et2)8,d-Ala10]-LH-RH [120], and Abarelix (PPI-149) [N-Ac-d-Nal(2)-d-(p-Cl)-Phe-d-Pal(3)-Ser-NM-Tyr-Asn-Leu-ILys-Pro-Gly-NH2 [115].

In Phase I clinical studies, Cetrorelix given i.v., subcutaneously (s.c.), or intramuscularly (i.m.) in doses of 300–1200 μg produced a prompt inhibition of LH and FSH release in postmenopausal women and caused no side effects [55]. Normal men showed a major fall in serum LH, FSH, and testosterone levels for 12–24 h after s.c. administration of 300 μg of Cetrorelix [55]. Behre et al. [8] and Klingmuller et al. [88] obtained similar effects with Cetrorelix in normal men. Cetrorelix appears to have the higher suppressive rate than other LH-RH antagonists and even in large doses of up to 10 mg only occasionally causes minimal erythema [8], [88].

LH-RH antagonists should have major uses in gynecology and oncology. LH-RH antagonists produce a competitive blockade of LH-RH receptors, preventing a stimulation by endogenous LH-RH, and cause an immediate inhibition of the release of gonadotropins and sex steroids [80], [139], [144], [149], [150], [151] in contrast to the LH-RH agonists that require repeated administration to achieve this effect. The advantage of the antagonists is based on the fact that they induce inhibition of LH, FSH, and sex steroid secretion from the start of the administration and greatly reduce the time of the onset of therapeutic effects. The use of antagonists prevents a clinical flare-up of disease caused by a transient LH and sex steroid release, which can occur in some cancer patients during initial agonist administration, even when microcapsules are used [80], [138], [144], [149], [150]. The principal mechanism of action of LH-RH antagonists was thought to be based on a competitive receptor occupancy of LH-RH receptors, but recently, we have demonstrated that chronic administration of LH-RH antagonist Cetrorelix to rats also produces desensitization of gonadotropes, down-regulation of pituitary LH-RH receptors, and a decrease in the levels of mRNA for LH-RH receptors [130]. Thus some mechanisms of down-regulation of pituitary LH-RH receptors produced by antagonists of LH-RH appear to be similar to those resulting from the agonists [130]. This view is supported by some clinical findings.

Initially, agonists of LH-RH were administered daily by the s.c. route or intranasally [150]. However, daily administration is inconvenient. Subsequently, long-acting delivery systems for [d-Trp6]LH-RH (Decapeptyl) and other agonists in microcapsules of poly(dl-lactide-co-glycolide) or different polymers were developed [31], [138], [144], [149], [150]. These microcapsules were designed to release a controlled dose of the peptide (usually 100 μg) over a 30-day period [138]. These spherical microcapsules contain 2–6% analog and 94–98% of biodegradable, biocompatible polymer. Other forms of sustained delivery system consist of microgranules (microparticles) of amorphous shape or cylindrical rods containing the peptide analogs.

For administration, the microcapsules or microgranules are suspended in an injection vehicle containing 2% carboxymethylcellulose or d-Mannitol and 1% Tween 20 or 80 in water and injected once per month i.m. through a 20-gauge needle. Preparations of Lupron depot microspheres containing 3.75–7.5 mg of Leuprorelin acetate injectable i.m., or of Zoladex (Goserelin, 3.6 mg) in cylindrical rods of the polymer poly(dl-lactide-co-glycolide) [31] injectable s.c. through a 16-gauge needle, and polyhydroxybutyrate tablets containing 3.6–5 mg of Buserelin, which is implantable s.c., are also available [31], [150]. Improved depot preparations, which release the analogs for 60–90 days, have been developed recently. Microcapsules and other sustained delivery systems permit the delivery of peptides into the blood stream at a controlled rate over an extended period of time. The delivery systems developed for administration of LH-RH analogs are practical and convenient and ensure patient compliance [150]. Sustained delivery systems for LH-RH antagonists Cetrorelix, Abarelix, and other antagonists also are being developed.

An additional new class of antitumor compounds based on LH-RH has been developed consisting of LH-RH analogs, mostly agonists, conjugated to a variety of chemotherapeutic agents [118], [157]. It is well known that in prostatic, breast, ovarian, and endometrial cancers conventional chemotherapy is associated with a high toxicity and a varying degree of response. Targeted chemotherapy may be more effective and would greatly reduce the peripheral toxicity of cytotoxic agents. The idea of a ‘magic bullet’ that could selectively eradicate tumors was originally conceived more than 100 years ago by Paul Ehrlich but remained unexplored for many decades [157]. On the basis of the presence of LH-RH receptors in breast, endometrial, ovarian, and prostatic cancers, we started some 10 years ago the development of targeted antitumor compounds by linking cytotoxic compounds to LH-RH analogs [6], [157], [158].

Early cytotoxic analogs consisting of various antineoplastic radicals such as d-melphalan, cisplatinum, and methotrexate linked to LH-RH analogs showed binding to prostatic, mammary, endometrial, and ovarian cancer cell lines and inhibited tumor growth in vitro and/or in vivo [6], [158]. In some of these early conjugates, doxorubicin (DOX), the most widely used anti-cancer agent, was linked to LH-RH analogs but, unfortunately, the activity of DOX within these hybrids was greatly reduced because of the nature of the linkage [6], [158].

Recently, we conjugated [d-Lys6]LH-RH through the ϵ-amino group of its d-Lys moiety and a glutaric acid spacer to the 14-OH group of DOX to form cytotoxic LH-RH analog AN-152 [118]. An even more potent cytotoxic analog (AN-207) (Fig. 4) was synthesized by linking 2-pyrrolino-DOX (AN-201), a daunosamine-modified derivative of DOX, which is 500–1000 times more active in vitro than its parent compound, to the same [d-Lys6]LH-RH carrier [118]. The antiproliferative activity of the cytotoxic radicals and the high binding affinity of the carrier to LH-RH receptors are both fully preserved in the cytotoxic LH-RH analogs AN-152 and AN-207 [118], [157]. We have shown that these new cytotoxic LH-RH analogs AN-152 and AN-207 powerfully inhibit growth of various experimental tumors. This approach, which remains to be tested clinically, could open up a new area of cancer therapy because the cytotoxic analogs developed might have the potential to produce an eventual cure.

LH-RH agonists have been used for more than 12 years in the assisted reproduction (in vitro fertilization and embryo transfer) programs to suppress pituitary-ovarian function [132], [179], [184]. Recently, Cetrorelix and other antagonists were applied successfully in women undergoing controlled ovarian stimulation procedures [2], [28], [30], [69], [99], [122], [123], [140], [175]. LH-RH antagonists appear to have advantages over the agonists for controlled ovarian stimulation-assisted reproduction technology programs.

The lowering of estrogen levels by administration of LH-RH agonists has been used for the management of endometriosis [48], [65], [111], [185] and for treatment of large ovarian endometriomas [23]. Only one incidence of flare-up of disease has been reported [58].

LH-RH agonists have been employed for more than 10 years for the treatment of infertility due to polycystic ovarian disease [3], [18], [43]. Recently, Hayes et al. showed that administration of an LH-RH antagonist can rapidly suppress LH, FSH, and testosterone levels in women with polycystic ovarian disease [62].

The induction of a state of hypoestrogenism by LH-RH agonists has been applied for a successful therapy of women with uterine leiomyomas (fibroids) [44], [49], [63], [104], [128], [176]. Recent results indicate that LH-RH antagonists also can be used for an efficacious medical management of uterine leiomyomas [42], [50], [85]. Administration of Cetrorelix produces a rapid regression of leiomyomas, and a hysterectomy can be avoided [42], [50].

Benign prostatic hypertrophy (BPH) affects many elderly men and may lead to urinary incontinence. For those patients who are poor operative risks, a nonsurgical treatment of BPH would be beneficial. When LH-RH agonists were tried for therapy of BPH [47], [129], a reduction in serum testosterone and a decrease in prostate size were obtained, but after the cessation of the treatment a regrowth of the prostate occurred [129]. Recent clinical trials indicate that LH-RH antagonists like Cetrorelix can produce a long-term improvement in patients with symptomatic BPH [19], [56]. Thus, in addition to lowering the levels of serum testosterone, Cetrorelix appears to exert some inhibitory effect on growth factors, as suggested by our experimental work [96], [150].

Various attempts have been made to develop methods for female contraception based on the use of LH-RH agonists and antagonists [13], [57], [121], [144], [149], [183], but clinical regimens are lacking. It is also doubtful that LH-RH agonists will be suitable as male contraceptives [10], [14], [64], [102]. The combined use of LH-RH antagonists and androgens for the suppression of spermatogenesis in men has been demonstrated [7], [8], [9], [174], but the acceptability of these methods for male contraception is questionable.

The efficacy of agonists of LH-RH for the treatment of children with precocious puberty is well established [20], [27], [61], [79], [84], [94], [106], [168]. The cessation of sexual development and other clinical benefits to children are clearly documented [20], [21], [27], [61], [79], [84], [94], [106], [168]. LH-RH antagonists have not been investigated in children with precocious puberty but could achieve a more rapid inhibition of pituitary-gonadal axis.

Section snippets

Endometrial cancer

Endometrial cancer is the second most common gynecologic cancer in the western world, ranking only behind breast cancer [39]. Surgery or radiotherapy is successful in 75% of cases, but new methods are needed for advanced (FIGO Stage III or IV) or relapsed cancers [39], [150]. Endometrial carcinoma is estrogen-dependent, and thus it should respond to therapy with LH-RH analogs [150]. In addition, high affinity receptors for LH-RH are present on nearly 80% of membranes of human endometrial

Acknowledgements

This article is dedicated to the memory of Geoffrey W. Harris, C.B.E., F.R.S, Dr. Lee’s Professor of Anatomy in the University of Oxford, who established the basic theories of hypothalamic control of the pituitary gland. A few months before his untimely passing, he had the satisfaction of seeing his brilliant concepts and life’s work confirmed by the isolation and identification of LH-RH.

Some original experimental work described in this paper was supported by the Medical Research Service of the

References (185)

  • D. Gonzalez–Barcena et al.

    Suppression of gonadotropin release in man by an inhibitory analogue of luteinizing hormone-releasing hormone

    Lancet

    (1977)
  • D. Gonzalez–Barcena et al.

    Luteinizing hormone-releasing hormone antagonist SB-75 (Cetrorelix) as primary single therapy in patients with advanced prostatic cancer and paraplegia due to metastatic invasion of spinal cord

    Urology

    (1995)
  • J.A. Gudmundsson et al.

    Inhibition of ovulation by intranasal Nafarelin, a new superactive agonist GnRH

    Contraception

    (1984)
  • L.L.H. Hall et al.

    Flare-up of endometriosis induced by gonadotropin-releasing hormone agonist leading to bowel obstruction

    Fertil Steril

    (1995)
  • G. Halmos et al.

    Cytotoxic analogs of luteinizing hormone-releasing hormone bind with high-affinity to human breast cancers

    Cancer Lett

    (1999)
  • A. Jungwirth et al.

    Inhibition of growth of androgen-independent DU-145 prostate cancer in vivo by LH-RH antagonist Cetrorelix and bombesin antagonists RC-3940-II and RC-3950-II

    Eur J Cancer

    (1997)
  • S.S. Kakar et al.

    The nucleotide sequences of human GnRH receptors in breast and ovarian tumors are identical with that found in pituitary

    Mol Cell Endocrinol

    (1994)
  • A.J. Kastin et al.

    Administration of LH-releasing hormone to selected human subjects

    Am J Obstet Gynecol

    (1970)
  • D. Kleinman et al.

    Regulation of endometrial cancer cell growth by insulin-like growth factors and luteinizing hormone-releasing hormone antagonist SB-75

    Reg Pept

    (1993)
  • J.G.M. Klijn et al.

    Treatment with a luteinizing hormone-releasing hormone analogue (Buserelin) in premenopausal patients with metastatic breast cancer

    Lancet

    (1982)
  • E. Knobil

    The neuroendocrine control of the menstrual cycle

    Recent Prog Horm Res

    (1980)
  • F. Labrie et al.

    Flutamide eliminates the risk of disease flare in prostatic cancer patients treated with a luteinizing hormone-releasing hormone agonist

    J Urol

    (1987)
  • N. Lamharzi et al.

    Luteinizing hormone-releasing hormone (LH-RH) antagonist Cetrorelix inhibits growth of DU-145 human androgen-independent prostate carcinoma in nude mice and suppresses the levels and mRNA expression of IGF-II in tumors

    Reg Pept

    (1998)
  • A. Lemay et al.

    Potential new treatment of endometriosisReversible inhibition of pituitary ovarian function by chronic intranasal administration of luteinizing hormone releasing hormone (LHRH) agonist

    Fertil Steril

    (1982)
  • I. Leroy et al.

    A single injection of a gonadotropin-releasing hormone (GnRH) antagonist (Cetrorelix) postpones the luteinizing hormone (LH) surgefurther evidence for the role of GnRH during the LH surge

    Fertil Steril

    (1994)
  • F.R. Ahmann et al.

    Zoladex. A sustained-release monthly luteinizing hormone-releasing hormone analogue for the treatment of advanced prostate cancer

    J Clin Oncol

    (1987)
  • D. Ayalon et al.

    Induction of ovulation with [d-Trp6]LHRH combined with purified FSH in patients with polycystic ovarian disease

    Gynecol Endocrinol

    (1988)
  • S. Bajusz et al.

    New antagonists of LHRH. II. Inhibition and potentiation of LHRH by closely related analogs

    Int J Peptide Prot Res

    (1988)
  • S. Bajusz et al.

    Highly potent analogs of luteinizing hormone-releasing hormone containing d-phenylalanine nitrogen mustard in position 6

    Proc Natl Acad Sci USA

    (1989)
  • H.M. Behre et al.

    Sustained suppression of serum LH, FSH and testosterone and increase of high-density lipoprotein cholesterol by daily injections of the GnRH antagonist cetrorelix over 8 days in normal men

    Clin Endocrinol

    (1994)
  • H.M. Behre et al.

    Effective suppression of luteinizing hormone and testosterone by single doses of the new gonadotropin-releasing hormone antagonist Cetrorelix (SB-75) in normal men

    J Clin Endocrinol Metab

    (1992)
  • H.M. Behre et al.

    High loading and low maintenance doses of a gonadotropin-releasing hormone antagonist effectively suppress serum luteinizing hormone, follicle-stimulating hormone, and testosterone in normal men

    J Clin Endocrinol Metab

    (1997)
  • H.M. Behre et al.

    Depot gonadotropin-releasing hormone agonist blunts the androgen-induced suppression of spermatogenesis in a clinical trial of male contraception

    J Clin Endocrinol Metab

    (1992)
  • P.E. Belchetz et al.

    Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone

    Science

    (1978)
  • C. Benson et al.

    National Cancer Institute study of luteinizing hormone-releasing hormone plus flutamide versus luteinizing hormone-releasing hormone plus placebo

    Semin Oncol

    (1991)
  • C. Bergquist et al.

    Intranasal gonadotrophin-releasing hormone agonist as a contraceptive agent

    Lancet

    (1979)
  • S. Bhasin et al.

    Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in the human male. III. Effects of long term combined treatment with GnRH agonist and androgen

    J Clin Endocrinol Metab

    (1985)
  • R. Burgus et al.

    Primary structure of the ovine hypothalamic luteinizing hormone-releasing factor (LRF)

    Proc Natl Acad Sci USA

    (1972)
  • E.S. Canales et al.

    Suppressive effect of an inhibitory LHRH analog on the gonadotropin response to LHRH in normal women

    Int J Fertil

    (1980)
  • R.J. Chang et al.

    Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin-releasing hormone agonist

    J Clin Endocrinol Metab

    (1984)
  • A.M. Comaru–Schally et al.

    Efficacy and safety of luteinizing hormone-releasing hormone antagonist Cetrorelix in the treatment of symptomatic benign prostatic hyperplasia

    J Clin Endocrinol Metab

    (1998)
  • F. Comite et al.

    Luteinizing hormone-releasing hormone analog treatment of boys with hypothalamic hamartoma and true precocious puberty

    J Clin Endocrinol Metab

    (1984)
  • P.M. Conn et al.

    Gonadotropin-releasing hormone and its analogs

    N Engl J Med

    (1991)
  • Corbin A, Beattie CW, Tracy J, Jones R, Foell TJ, Yardley J, Rees RWA. The anti-reproductive pharmacology of LHRH and...
  • J. Cortes–Prieto et al.

    Long-acting agonists of LH-RH in the treatment of large ovarian endometriomas

    Int J Fertil

    (1987)
  • D.H. Coy et al.

    Analogs of luteinizing hormone-releasing hormone with increased biological activity produced by d-amino acid substitutions in position 6

    J Med Chem

    (1976)
  • E.D. Crawford

    Hormonal therapy of prostatic carcinoma. Defining the challenge

    Cancer

    (1990)
  • E.D. Crawford et al.

    A controlled trial of leuprolide with and without flutamide in prostatic carcinoma

    N Engl J Med

    (1989)
  • W.F. Crowley et al.

    Therapeutic use of pituitary desensitization with a long-acting LHRH agonista potential new treatment for idiopathic precocious puberty

    J Clin Endocrinol Metab

    (1981)
  • K. Diedrich et al.

    Suppression of the endogenous luteinizing hormone surge by the gonadotrophin-releasing hormone antagonist Cetrorelix during ovarian stimulation

    Hum Reprod

    (1994)
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