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Gonadotropin-releasing hormone (GnRH) acts by regulating circulating concentrations of hypothalamic-pituitary-gonadal (HPG) hormones. Leuprolide (or leuprorelin) was the first GnRH agonist to enter clinical development for a variety of clinical indications. Commercialized as leuprolide acetate, leuprolide acetate (5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate) is a synthetic GnRH peptide analog that resembles natural GnRH with receptor agonist activity. Continuous administration of leuprolide inhibits pituitary gonadotropin secretion and inhibits testicular and ovarian steroidogenesis, and is more potent and has a longer half-life than GnRH.
Figure 1. Leuprolide acetate
(Source: Teutonico D, et al. 2012)
Natural GnRH is secreted from the hypothalamus in a pulsatile manner, and the frequency of the pulses determines whether the pituitary gland secretes follicle-stimulating hormone (FSH) or luteinizing hormone (LH). GnRH agonists provide sustained stimulation of the GnRH receptor, which is desensitized after an initial stimulation phase, resulting in severe suppression of gonadotropins and ovarian steroids. This unexpected effect provides a rationale for suppressive therapy in a variety of clinical indications.
Figure 2. Mechanism of action of gonadotropin-releasing hormone antagonists versus gonadotropin-releasing hormone agonists
(Source: Taylor HS, et al. 2019)
Endometriosis is an estrogen-dependent disease, and GnRH agonists have been shown to be effective in reducing the pelvic pain associated with endometriosis. However, treatment with GnRH agonists produces serious hypoestrogenic side effects, including progressive bone loss and vasomotor symptoms such as hot flashes and vaginal dryness. As early as the early 1990s, several hormone add-back therapies (including different estrogen-progestin combinations, and estrogen monotherapy) were shown to improve symptoms of hypoestrogenism in women with endometriosis treated with GnRH agonists without significantly affecting efficacy.
To assess the efficacy and safety of leuprolide acetate alone and in combination with 3 hormone add-on therapies, a 12-month study in 201 female patients with endometriosis-related pelvic pain found that leuprolide acetate with norethindrone acetate (NETA) or in combination with NETA and conjugated equine estrogens (CEE) were effective in suppressing pelvic pain associated with endometriosis while preventing bone loss. In the prevention of bone loss, 5 mg of NETA was as effective as 5 mg of NETA plus a moderate dose (0.625 mg of CEE) or a high dose of estrogen (1.25 mg of CEE). NETA is a unique progestin with both estrogenic (as a prodrug of the potent estrogen ethinyl estradiol) and androgenic properties, primarily through its estrogenic activity, that exerts beneficial effects on bone density and vasomotor symptoms in women receiving acetate. The efficacy of leuprolide as an add-back therapy is explained by its beneficial effects on bone density and vasomotor symptoms in women treated with leuprolide.
Figure 3. Potential mechanism of action of NETA as an add-back therapy to GnRH agonist in women with endometriosis.
(Source: Chwalisz K, et al. 2012)
Leuprolide may be used as a preoperative treatment for uterine fibroids (hysterectomy, myomectomy, endometrial ablation) in women with anemia due to prolonged or excessive bleeding caused by uterine fibroids. In a clinical Phase III trial comparing the efficacy of leuprolide acetate in combination with iron versus iron alone, it was found that a significantly higher proportion of women responded to treatment in the leuprolide acetate group (combination group) than in the placebo group (iron alone group). Women treated with leuprolide acetate also experienced a significant reduction in uterine and fibroid size compared to the placebo group. The main adverse effects in the leuprolide acetate group were hot flashes and vaginitis.
The combination of leuprolide acetate and iron is more effective than iron alone in treating anemia, reducing fibroid volume, and alleviating bleeding and other fibroid-related symptoms (bloating, pelvic pain, and pelvic pressure) in patients with uterine fibroids. Improving anemia may make women with heavy uterine bleeding and fibroids better surgical candidates, as they may no longer require preoperative blood transfusions and may become autologous blood donors. Similarly, a reduction in the size of fibroids may affect the type of surgery (such as myomectomy versus hysterectomy). According to this study, leuprolide acetate in combination with iron has been approved by the U.S. Food and Drug Administration to improve preoperative hematology in women with anemia due to uterine fibroids who necessitate hormone suppression for 3 months.
Androgen deprivation therapy (ADT) using a GnRH agonist is a well-recognized first-line therapy for the treatment of advanced/metastatic prostate cancer (PCa) and is recommended before, during, or after definitive radiotherapy for intermediate- and high-risk localized prostate cancer.
ADT reduces serum testosterone (T) levels (T is a promoter of prostate cancer growth), improves overall survival and relieves symptoms in PCa patients. Leuprolide consistently reduces serum testosterone to castration level aspects in men with advanced prostate cancer. However, GnRH agonist-induced ADT is associated with an increased incidence of hypoandrogenic adverse events and an increased risk of metabolic and cardiovascular disease.
Table 1. Therapeutic classes and agents approved for prostate cancer
| Class | Target | Agent | Mechanism of action | Indication(s) | Notable side effects |
| Nonsteroidal androgen receptor antagonist (first generation) | Androgen receptor | Bicalutamide, flutamide, nilutamide | Competitively and reversibly inhibit binding of testosterone and DHT to ligand binding domain of androgen receptor | In combination with GnRH agonists in metastatic disease | Hot flashes, pain, infection, abdominal pain |
| Androgen biosynthesis inhibitor | Steroidal enzyme CYP17A1 (17 alpha-hydroxylase/C17, 20 lyase) | Abiraterone | Abiraterone acetate (prodrug) converted in vivo to abiraterone which inhibits CYP17A1 expressed in adrenal, testicles and prostate tumor | mCRPC, mCSPC (in combination with prednisone and ADT) | Hypokalemia, hypertension, edema, adrenal insufficiency, hepatotoxicity |
| GnRH antagonists | GnRH receptor | Degarelix, relugolix | Competitively and reversibly inhibit GnRH receptors in pituitary gland which blocks release of FSH and LH | Advanced prostate cancer | Injection site reaction (degarelix), hot flashes, fatigue, weight gain, hepatotoxicity |
| GnRH agonists | GnRH receptor | Histrelin, goserelin, leuprolide, triptorelin | Continuous stimulation of GnRH receptor that leads to initial surge in FSH, LH, testosterone, and DHT followed by reductions | Advanced prostate cancer (including mCRPC) | General pain, hot flashes and sweating, gastrointestinal disorders |
Abbreviations: ADT-androgen deprivation therapy; mCRPC-metastatic castration-resistant prostate; DHT-5α-dihydrotestosterone; FSH- follicle-stimulating hormone; LH- luteinizing hormone; GnRH- gonadotropin-releasing hormone.
(Source: Desai K, et al. 2021)
Central precocious puberty (CPP) is the result of premature activation of the hypothalamic-pituitary-gonadal axis during puberty, which leads to a pulsatile release of GnRH and premature secretion of gonadal steroids in girls and boys. Treatment with GnRH agonists, which has been the standard treatment for CPP, results in hormonal suppression, cessation of pubertal development, and normalization of growth and skeletal maturation rates. Leuprolide acetate was the first GnRH agonist used to treat CPP. It initially took the form of monthly intramuscular injections (7.5mg, 11.25mg, and 15mg) and later evolved to 3-monthly intramuscular injections (11.25mg and 30mg).
The therapeutic dose was determined through a clinical Phase III study that evaluated biochemical (peak stimulated luteinizing hormone, estradiol in girls, and testosterone in boys) and anthropometric (growth rate, accelerated bone age, pubertal progression) parameters and safety. The safety and efficacy of a 1-month formulation of leuprolide acetate has been demonstrated in pediatric patients with CPP. The 3-month formulation of leuprolide acetate was evaluated and shown to be effective in suppressing the GnRH axis and positively affecting patient convenience and compliance. Both treatments were well tolerated, with the most common treatment adverse effect being injection site pain.
References
| Target | Cat. No. | Product Name | Size | Species Reactivity | Application | Detection Sample | |
| Leuprolide | DEIA-XYZ93 | Leuprolide High Sensitivity ELISA Kit | 96T | Quantitative | Serum, plasma | Inquiry |
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