Roles of Goserelin in Gynecological Disorders

Central precocious puberty (CPP), also known as gonadotropin dependent precocious puberty, is the early onset of puberty caused by premature activation of the hypothalamic-pituitary-gonadal axis. The aim of CPP treatment includes to suppress puberty progression, to normalize the rates of height growth and bone age advance, and to preserve patients’ adult height potential. GnRH agonists can halt puberty progression by suppressing the premature secretion of sex hormones and have been used for CPP management since the 1980s. 165 In children with CPP, goserelin brings about rapid initial growth deceleration, an effect reported in a retrospective cohort as significantly greater than that of leuprolide over the first 6 months of treatment (change in height standard deviation score [SDS] -0.2 [n=17] vs 0.003 [n=23], P =0.025). 166 Goserelin 3.6 mg and 10.8 mg both can effectively suppress pubertal development and decelerate height growth and bone age advance over 1–2 years of treatment, 165 , 167 although a retrospective study reported that to achieve adequate suppression, a larger proportion of patients required more frequent injections with goserelin 10.8 mg (71% [20/28] at 6–10-week intervals) than with goserelin 3.6 mg (44% [15/34] at 3-week intervals). 167 A cohort study observed that in patients receiving goserelin 10.8 mg, those with prior goserelin exposure experienced significant increases in peak LH and FSH between weeks 8 and 12, showing a significantly higher week-12 median peak FSH level compared to patients on de novo goserelin treatment (1.6 IU/L [n=15] vs 1.0 IU/L [n=24]); this waning of gonadotropin suppression towards the end of the treatment cycle likely underlies the need for more frequent injection. 168 Increases in BMI during goserelin treatment have been reported, 166 , 167 , 169 especially for goserelin 10.8 mg. 167 In a retrospective study of 46 girls with CPP or early puberty, mean BMI SDS increased significantly from 0.93 to 1.2 during treatment with goserelin 10.8 mg (median treatment duration: 2.9 years), but the mean BMI SDS returned to before-treatment level for the 11 girls who reached final heights (1.18 before treatment; 1.41 at the end of treatment; 1.16 at final height); notably, 9 of the 11 girls attained final heights within or above their target range. 169

Goserelin is a gonadotropin-releasing hormone (GnRH) agonist with a long history and a wide geographic span of clinical application, whereby its efficacy and safety have been well proven. Goserelin is on the Essential Medicines List published by the World Health Organization. 1 Administered subcutaneously in the form of a biodegradable lactide-glycolide co-polymer rod, goserelin depot is available in two dosages, namely 3.6 mg once a month and 10.8 mg once every 3 months. 2 The past three decades have seen the use of goserelin in an increasing number of indications. Although first approved and still an important treatment for prostate cancer, goserelin has found wider applications as an important therapy in breast cancer and gynecology. 2 Approved gynecological indications of goserelin include endometriosis, uterine fibroids, usage as an agent for endometrial thinning, and usage as an agent for ovarian downregulation prior to assisted reproduction. More recent research continues to explore the use of goserelin in expanded gynecological diseases, such as adenomyosis and female cancers. Over the course of long clinical application, new experience has been gained about the optimal use of goserelin. For example, alternative administration schedules different from the conventional timing of days 1–5 of the menstrual cycle have been explored, with the additional benefit of reduced uterine bleeding demonstrated in certain scenarios. Moreover, goserelin may be a versatile and useful tool in clinical scenarios where gynecologic management is required as part of multi-disciplinary therapy. This article will take inventory of the use of goserelin in gynecological disorders, both in the traditional indications and in the newly established and/or emerging therapeutic areas. The subsequent discussions on goserelin refer to the 3.6 mg formulation, unless otherwise specified.

Goserelin is generally safe and well tolerated, especially if used with add-back therapy to attenuate the symptoms of the induced menopause-like state, such as hot flashes, night sweats, mood swings and vaginal dryness. The impact of prolonged goserelin treatment on BMD is the safety issue receiving most attention. Add-back hormonal replacement therapy (HRT) can help reduce the bone loss during long-term goserelin treatment. In young women with endometriosis or female cancers, the use of goserelin is generally associated with bone loss to some extent; add-back therapy can be used to counter this effect for patients with endometriosis but usually not for cancer patients. For treating adolescent endometriosis with secondary dysmenorrhea or acyclic and/or cyclic pelvic pain, GnRH agonists can be used with caution, with age limits of 16 or 17 years old and with add-back therapy required; 170–173 some also consider it necessary to monitor BMD in adolescent patients at the end of 9–12 months of GnRH agonist treatment and at least every two years if the treatment is prolonged. 171 In patients aged >40 years with uterine myomas, significant bone loss (-4.4%–-7.6%) was observed after 12-month goserelin treatment, which was reversed slightly 6 months after treatment. 174 In a prospective randomized study, patients with chronic cyclical pelvic pain received goserelin 10.8 mg for 18 months with HRT initiated either immediately or with a 6-month delay. 175 Both groups showed similar BMD decreases at 18 months (-1.167%–-4.617% vs -2.990%–-4.730%), which were partially reversed 12 months after treatment cessation (-0.783%–-3.865% vs -2.992%–-3.290%). 175 In patients with breast cancer, 2-year OFS with goserelin without HRT led to a significant reduction in BMD (-5%), which partially recovered (by 1.5%) 1 year after treatment cessation. 176 In another prospective partially-randomized study of endometriosis, BMD reduction occurred during long-term goserelin use and was not fully recovered by up to 6 years after treatment, and use of HRT did not affect this process. 177 The lack of benefit of HRT on BMD recovery observed in that study may be attributable to bias introduced by the partially randomized design, in which patients could choose whether to receive HRT and only those without a preference were randomized. 177 More well-designed clinical research is warranted to reconcile these seemingly contradictory findings regarding long-term BMD recovery after goserelin treatment.

The classical mechanism of pituitary-ovarian gonadal axis downregulation underlies the wide-ranging utility of goserelin in hormone-dependent conditions. Continuous administration of goserelin induces the desensitization of pituitary GnRH receptors and the downregulation of gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]), which in turn leads to ovarian function suppression and reduces estrogen and progesterone to postmenopausal levels. 2 In benign gynecological conditions, the local overexpression of inflammatory cytokines has been implicated in the pathogenic processes of cell proliferation, angiogenesis and accumulation of extracellular matrix. Goserelin can reduce the levels of pro-inflammatory cytokines and growth factors such as IL-8, PAPP-A, glycodelin-A and midkine, and effect a regression of the inflammatory microenvironment. 3 Some evidence suggests that such anti-inflammatory effect may arise from direct interactions with local GnRH receptors, over and above the effect of a hypoestrogenic state. 4 Recent molecular docking studies in endometriosis identified transcription factors and immune-related proteins as potential targets of goserelin, including the proinflammatory CXCL12, SCG2, 5 AEBP1 and HOXB6, 6 as well as the anti-inflammatory KLF2 and RORB, 6 although these remain to be validated biochemically. Some molecular pathways have been identified for mediating direct anti-tumor effects of goserelin. In vitro and xenograft model studies showed that goserelin could promote apoptosis by upregulating the expression of FOXO1 through the PI3K/AKT pathway in epithelial ovarian cancer cells, 7 and can inhibit the growth of prostate cancer cells by attenuating EGFR signaling. 8 The native GnRH is a decapeptide folded around the flexible glycine at position 6 (Gly6) when bound to the GnRH receptor. 9 Replacing Gly6 with a D-amino acid improves the conformational stability of the decapeptide, thereby enhancing its binding affinity to GnRH receptors and resistance to enzymatic degradation: this has formed the principle underlying the development of all GnRH agonists such as triptorelin, leuprorelin, buserelin, and goserelin ( Figure 1 ). 9 In goserelin, the amino acid at position 6 is a D-Ser(tBu); additionally, the glycine at position 10 of the native GnRH is replaced by an aza-glycine (azaGly10) in goserelin. Compared to buserelin, which similarly has D-Ser(tBu)6 but with Pro9-nET instead of Pro9-azaGly10, goserelin is considered at least 5 times more potent as measured by induction of ovulation. 10 Figure 1 Amino acid sequence of GnRH and selected GnRH agonists. GnRH gonadotropin-releasing hormone. Adapted from Millar et al (2004), 9 copyright 2004 The Endocrine Society. The image shows a comparison of amino acid sequences for gonadotropin-releasing hormone and its agonists: triptorelin, leuprorelin, buserelin and goserelin. Each row represents a sequence with specific amino acids highlighted. The sequence for gonadotropin-releasing hormone includes pGlu, His, Trp, Ser, Tyr, Gly, Leu, Arg, Pro and Gly. Triptorelin replaces Gly with D-Trp. Leuprorelin replaces Gly with D-Leu. Buserelin replaces Gly with DSer(tBu). Goserelin replaces Gly with DSer(tBu) and the final Gly with AzaGly. The sequences are visually represented with circles for each amino acid and modifications are highlighted. Comparison of amino acid sequences for GnRH and its agonists: triptorelin, leuprorelin, buserelin and goserelin. Amino acid sequence of GnRH and selected GnRH agonists. GnRH gonadotropin-releasing hormone. Adapted from Millar et al (2004), 9 copyright 2004 The Endocrine Society. Dose-ranging studies using goserelin depots of 0.9 mg, 1.8 mg and 3.6 mg revealed a dose-proportional serum concentration profile of goserelin. 2 The 3.6 mg depot has a release rate of 120 µg/day, which is sustained consistently over the course of 4 weeks. 2 Successive dosing of goserelin 3.6 mg depot at a 4-week interval yielded consistent serum concentration profiles between doses; comparisons of the area under the concentration-time curve (AUC) values of goserelin between the aqueous and the depot formulations indicate a 100% relative bioavailability of goserelin from the 3.6 mg depot and a complete goserelin release from the depot over 4 weeks. 11 In hepatically impaired individuals, the plasma elimination half-life and clearance of goserelin (in a research aqueous formulation), as well as the bodyweight normalized AUC, were not significantly different from those in age-matched healthy volunteers. 2 For patients with several renal impairment (investigated in prostate cancer patients), the body clearance of goserelin (in a research aqueous formulation) was reduced (1.9 L/h, vs 8 L/h with normal renal function) but still sufficient to avoid drug accumulation. 2 Thus, no dose adjustment of goserelin is required in patients with renal or hepatic dysfunction. In females, following the injection of a goserelin 3.6 mg depot, the serum LH and FSH levels rise sharply before rapidly decreasing to below baseline level by day 3, and remain markedly suppressed from day 8 onward. 11 The levels of estradiol show a transient rise 3 days after goserelin depot administration, decrease to postmenopausal levels by week 1, and remained suppressed with successive administration of goserelin depot. Similarly, serum progesterone level peaks 2 days after administration of goserelin depot and becomes complete suppressed by day 14. 11

Goserelin has proved to be a reliable and versatile drug in an ever-expanding range of gynecological conditions. In benign gynecological conditions, goserelin provides rapid symptom relief, reduction of lesion and uterine sizes, facilitation of surgical therapy, and improved fertility outcomes. Its utility also extends to rare variants of benign gynecological conditions. In female cancers, goserelin plays an established role as adjuvant therapy in premenopausal patients with ER-positive breast cancer. Emerging evidence supports its use in fertility-sparing treatment of early-stage endometrial cancer and in the management of recurrent and/or advanced ovarian cancer, while its potential in cervical cancer and advanced or recurrent endometrial cancer awaits further investigation. Across oncology and benign indications, goserelin also provides ovarian function protection for patients at risk of ovarian toxicity from chemotherapy. Prolonged use of goserelin leads to BMD losses, which can be managed using add-back therapies, are partially reversible after treatment cessation, and are often outweighed by the benefits of goserelin treatment including improvements in patients’ quality of life. Collectively, the expanding body of evidence underscores goserelin’s continued relevance as a flexible and valuable agent in contemporary gynecologic practice.