Pituitary-Gonadal Axis

LHRH analogs are widely used in oncology, and their mode of action is almost completely understood. The mechanism of action of these analogs is mainly based on the inhibition of pituitary and gonadal function, but direct effects on various tumors may also play a role.^5,6,21 Continuous treatment with LHRH agonists causes a downregulation (a decrease in the number) of LHRH receptors and an uncoupling of the LHRH signal transduction mechanism.^5,21,38 This results in a desensitization of gonadotrophs and a marked reduction in the secretion of bioactive LH and FSH.¹¹ This state is reversible and is called “selective medical hypophysectomy.”^5,21 The decrease in circulating LH and FSH, together with downregulation of gonadal receptors for LH and FSH, produces a complete inhibition of testicular or ovarian function and a fall in sex-steroid levels. This state is called “chemical or medical castration.”^5,21,39 The key advantage of the medical castration achieved by LHRH agonists is its reversibility.^5,21 In addition, various extrapituitary tissues, including the prostate, breast, uterus, and ovaries, as well as many tumors, contain specific receptors for LHRH, which might permit direct inhibitory actions of LHRH analogs.^{5,8,21,36,40–42}

The principal mechanism of action of LHRH antagonists is the competitive occupancy of LHRH receptors, but recent experimental evidence documents that treatment with the LHRH antagonist cetrorelix also downregulates pituitary LHRH receptors in rats and decreases the levels of mRNA for LHRH receptors.^5,8,21,43 These phenomena may also occur clinically.^5,8,22 The downregulation of pituitary LHRH receptors is also reversible, and a complete recovery occurs 1 to 2 months after cessation of treatment with antagonists.^5,21

The effects of LHRH agonists were evaluated in a variety of studies carried out since 1976. In the female rat, chronic administration of LHRH agonists decreased the ovarian and uterine weights, reduced the concentration of plasma estradiol and progesterone, and produced various antifertility effects.^3,5,21 The administration of LHRH agonists to premenopausal women initially increases plasma levels of gonadotropin, estradiol, and progesterone. However, after several weeks of administration of LHRH agonists, sex steroid levels are reduced to the postmenopausal range, but plasma estrone, androstanedione, and testosterone, although decreased, are somewhat above the levels in ovariectomized or postmenopausal women.^5,19,21 The effects of Decapeptyl, Zoladex, buserelin, and leuprolide are similar¹⁹ although the response to analogs may vary as a function of potency, Decapeptyl being apparently the most potent.⁵

The chronic administration of LHRH agonists to male rats was shown to result in decreased plasma gonadotropin and testosterone levels, as well as in atrophy of testes, seminal vesicles, and prostatic tissue.⁵ Administration of LHRH agonists to men initially results in a rise of FSH, LH, and testosterone, but after 4 to 6 weeks of treatment, plasma testosterone levels are reduced to castration levels.⁵

The mechanism of pituitary LH release in response to LHRH is not completely understood. The first step in the action of LHRH involves its binding to a plasma membrane receptor, which causes a microaggregation of receptors and complex formation.^38,44 The complex formed is then internalized and degraded although this internalization is not necessary for the liberation of the gonadotropins. Calcium and the products of phosphoinositide metabolism have been implicated as second messengers.^38,44 The LHRH receptor is coupled to a guanosine triphosphate (GTP)-binding protein (G protein) that can activate phospholipase C, which leads to the production of diacylglycerol and the activation of protein kinase C.^38,44 Recent studies show that multiple G proteins are involved in the action of LHRH on the gonadotrope. Activation of G protein stimulates LH release and inositol phosphate production.^38,44 The complete mechanisms still remain to be elucidated.

Direct Effects

Clinical evidence indicates that in patients with advanced breast or prostate cancer, medical castration produced by the chronic administration of LHRH analogs accounts for most benefits derived from the treatment.^5,21,44 However, there is also evidence that LHRH agonists and antagonists can exert direct effects on tumor cells.^5,21 This view is based on clinical results, the detection of high-affinity binding sites for LHRH in various cancers, and the effects on tumor cell lines in cultures.

Medical castration should not benefit postmenopausal women with breast cancer. However, various investigators^5,21,44–46 report responses in postmenopausal women with breast cancer treated with LHRH agonists. Recently, Saphner and colleagues obtained an 11% response rate in postmenopausal women treated with Zoladex.⁴⁷ Similarly, medical castration should not benefit patients with estrogen receptor (ER)-negative tumors, but responses in ER-negative premenopausal patients treated with leuprolide or Zoladex were recorded.^16,18

Receptors for LHRH in Various Tumors

Direct effects of LHRH analogs are most likely mediated by receptors found on tumor cells. Specific membrane receptors for LHRH have been found in various animal and human cancers.^8,40–42 Binding sites for LHRH were detected in LNCaP and DU 145 human prostate cancer lines and in Dunning rat prostate cancers.^48,49 More than 80% of human prostate cancer specimens exhibit high-affinity receptors for [D-Trp⁶]-LHRH.^5,8,41 Various investigators found LHRH receptors in several human mammary carcinoma cell lines.^5,8,44,49,50 LHRH membrane receptor sites were also detected in 260 of 500 samples of human breast cancer (52%).⁴⁰ LHRH receptors were found in 78% of human ovarian epithelial cancer specimens and in EFO-21, EFO-27, and OV-1063 human ovarian cancer lines.^21,42 Similarly, in nearly 80% of human endometrial carcinomas and in HEC-1A and Ishikawa endometrial cancer lines, the presence of receptors for [D-Trp⁶]-LHRH was established.²¹ LHRH receptors are also found in human pancreatic cancers.^3,5,51 The expression of LHRH receptor gene in human breast, ovarian, and prostate cancer cell lines was also demonstrated.^5,21,52–54 These findings provide a rationale for therapeutic approaches based on LHRH analogs in malignancies in which specific receptors for LHRH are found.

Inhibition of Growth of Tumor Cell Lines

Observations on growth inhibition of cultured tumor cells by LHRH analogs strongly support the concept of their direct effects. Significant inhibition of human breast and prostatic cancer cells by LHRH agonists in vitro is now well documented.^{5,8,48–50,52,55} The LHRH antagonist cetrorelix also causes a marked inhibition of proliferation of mammary, ovarian, and endometrial cancer cell lines.^{5,8,21,44,55,56} These results suggest a regulatory role of LHRH-like peptides in tumor growth. LHRH is not present in the general circulation in significant concentrations, but the presence of LHRH immunoreactivity and mRNA for LHRH in human mammary cancer cells suggests that local LHRH may play a role in the growth of mammary tumors.⁵² Subsequently, the evidence for production of an LHRH-like peptide and/or expression of mRNA for LHRH was obtained in human prostatic, endometrial, and ovarian cancer lines.^5,44,53,54 These LHRH-like peptides could function as local regulators of tumor growth. LHRH agonists and antagonists might inhibit the growth of tumor cells in part by nullifying the action of endogenous LHRH-like peptides.