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Concept: Gonadotropin-releasing hormone agonist

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Myomectomy has potential risks of complications. To reduce these risks, medical pre-treatment can be applied to reduce fibroid size and thereby potentially decrease intra-operative blood loss, the need for blood transfusion and emergency hysterectomy. The aim of this systematic review and meta-analysis is to study the effectiveness of medical pre-treatment with Gonadotropin-releasing hormone agonists (GnRHa) or ulipristal acetate prior to laparoscopic or laparotomic myomectomy on intra-operative and post-operative outcomes.

Concepts: Blood, Systematic review, Surgery, Hematology, Decision theory, Blood transfusion, Uterine fibroids, Gonadotropin-releasing hormone agonist

86

Background Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies. Methods We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary. Results A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings. Conclusions Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670 .).

Concepts: Therapeutic effect, Clinical trial, Estrogen, Menstrual cycle, Placebo, Acupuncture, Endometriosis, Gonadotropin-releasing hormone agonist

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Before planning an assisted conception treatment cycle, a thorough assessment of the woman’s hormone profile and ovarian reserve is essential to aid the decision on the appropriate protocol for controlled ovarian hyperstimulation (COH). There is insufficient evidence to recommend the use of one type of gonadotrophins over another. There is no benefit of luteinising hormone (LH) supplementation in cycles stimulated with follicle stimulating hormone alone in an unselected population. There is some evidence to suggest a potential benefit of LH supplementation in patients with a history of poor ovarian response to stimulation and in those older than 35 years. The long gonadotrophin releasing hormone (GnRH) agonist protocol is the most widely used and is the preferred protocol in the unselected population of women undergoing COH for in vitro fertilisation or intra-cytoplasmic sperm injection. The GnRH antagonist protocol is best used for known or suspected high responders, including women with PCOS, as it reduces the risk of OHSS. There is a lack of robust evidence to suggest that the GnRH agonist protocol is better than the GnRH antagonist protocol in poor responders. The prolonged GnRH agonist protocol is advantageous in women who are undergoing COH due to pelvic endometriosis. Oral contraceptive pill pre-treatment adversely affects the IVF outcome in GnRH antagonist cycles, but not in GnRH agonist cycles.

Concepts: Combined oral contraceptive pill, Luteinizing hormone, In vitro fertilisation, Follicle-stimulating hormone, Ovarian hyperstimulation syndrome, Fertility medicine, Gonadotropin-releasing hormone, Gonadotropin-releasing hormone agonist

25

BackgroundAdditional treatment with a gonadotropin-releasing hormone (GnRH) agonist (GnRHa) before IVF-ET (ultralong GnRHa therapy) has been reported to improve the outcome of IVF-ET in endometriosis patients. However, the mechanism of ultralong GnRHa therapy is unclear. It is suggested that inflammatory cytokines and oxidative stress contribute to infertility in endometriosis patients. Therefore, in order to search a possible mechanism of ultralong GnRHa therapy, we investigated the effect of ultralong GnRHa therapy on intrafollicular concentrations of tumor necrosis factor alpha (TNF¿), oxidative stress markers, and antioxidants in patients with endometriosis.MethodsTwenty-three infertile women with Stage III or IV endometriosis were recruited for this study. Eleven patients received three courses of GnRHa (1.8 mg s.c. every 28 days), followed by a standard controlled ovarian hyperstimulation (COH) for IVF-ET (ultralong group). The other 12 patients received a standard COH with mid-luteal phase GnRHa down-regulation (control group). The numbers of matured follicles and retrieved oocytes, fertilization rates, implantation rates, clinical pregnancy rate, and intrafollicular concentrations of TNF¿, 8-hydroxy-2¿-deoxyguanosine (8-OHdG) and hexanoyl-lysine adduct (HEL) as oxidative stress markers, and melatonin and Cu,Zu-superoxide dismutase (Cu,Zn-SOD) as antioxidants were compared between the two groups.ResultsThe numbers of mature follicles and retrieved oocytes, and fertilization rates did not differ between the two groups. Implantation rates and pregnancy rates tended to be higher in the ultralong group (21.4% and 27.3%, respectively) compared with the control group (8.3% and 8.3%, respectively). TNF¿ concentrations in the follicular fluid were significantly lower in the ultralong group (5.8¿±¿3.2 pg/ml) than those in the control group (10.6¿±¿3.2 pg/ml). Follicular concentrations of 8-OHdG concentrations were significantly lower in the ultralong group (5.7¿±¿1.6 ng/ml) than those in the control group (6.6¿±¿1.5 ng/ml), while melatonin concentrations were significantly higher in the ultralong group (139¿±¿46 pg/ml) compared with the control group (86¿±¿27 pg/ml).ConclusionsUltralong GnRHa therapy reduces the detrimental effects of cytotoxic cytokines and oxidative stress in the ovary in patients with endometriosis.

Concepts: Pregnancy, Oxidative stress, Infertility, In vitro fertilisation, Ovulation, Tumor necrosis factor-alpha, Gonadotropin-releasing hormone, Gonadotropin-releasing hormone agonist

16

In the treatment of women with abnormal uterine bleeding, once a thorough history, physical exam and indicated imaging studies are performed, and all significant structural causes are excluded, medical management is the first line approach. Determining the acuity of the bleeding, the patient’s medical history, assessing risk factors, and establishing a diagnosis will individualize their medical regimen. In acute abnormal uterine bleeding with a normal uterus parenteral estrogen, multi-dose combined oral contraceptives regimen, multi-dose progestin only regimen and tranexamic acid are all viable options given the appropriate clinical scenario. Heavy menstrual bleeding can be treated with levonorgestrel-releasing intrauterine system, combined oral contraceptives, continuous oral progestins and tranexamic acid with high efficacy. Nonsteroidal anti-inflammatory drugs may be utilized with hormonal methods and tranexamic acid to decrease menstrual bleeding. Gonadotropin-releasing hormone agonists are indicated in patients with leiomyoma and abnormal uterine bleeding in preparation for surgical interventions. In women with inherited bleeding disorders all hormonal methods as well as tranexamic acid can be used to treat abnormal uterine bleeding. Women on anticoagulation therapy should consider using progestin only methods as well as a gonadotropin-releasing hormone agonist to treat their heavy menstrual bleeding. Given these myriad options for medical treatment of abnormal uterine bleeding, many patients may avoid surgical intervention.

Concepts: Pregnancy, Hormonal contraception, Combined oral contraceptive pill, Menopause, Non-steroidal anti-inflammatory drug, Paracetamol, Menstruation, Gonadotropin-releasing hormone agonist

6

The Endocrine Society and the World Professional Association for Transgender Health published guidelines for the treatment of adolescents with gender dysphoria (GD). The guidelines recommend the use of gonadotropin-releasing hormone agonists in adolescence to suppress puberty. However, in actual practice, no consensus exists whether to use these early medical interventions. The aim of this study was to explicate the considerations of proponents and opponents of puberty suppression in GD to move forward the ethical debate.

Concepts: Endocrinology, Puberty, Gonadotropin-releasing hormone agonist

3

In observational studies, men with prostate cancer treated with gonadotropin-releasing hormone (GnRH) agonists had a higher risk of cardiovascular disease (CVD) compared to men who had undergone orchiectomy. However, selection bias may have influenced the difference in risk.

Concepts: Scientific method, Cancer, Disease, Metastasis, Prostate cancer, Gonadotropin-releasing hormone agonist

2

We have reported previously that after 1-year follow up, gonadotropin-releasing hormone agonist (GnRHa) did not prevent chemotherapy-induced premature ovarian failure (POF) in patients with lymphoma, but may provide protection of the ovarian reserve. Here, we report the final analysis of the cohort after 5 years of follow up.

Concepts: Randomized controlled trial, Menopause, Endocrinology, Fertility, Gynecology, Gonadotropin-releasing hormone agonist, Poor ovarian reserve, Premature ovarian failure

1

The World Professional Association for Transgender Health’s standards of care recommend suspending puberty, preferably with the use of gonadotropin-releasing hormone agonists, in certain gender non-conforming minors (aged under 18 years) who have undergone a psychiatric assessment and have reached at least Tanner stage II of puberty. This approach seeks to lessen the discordance between assigned natal sex and gender identity by temporarily halting the development of secondary sexual characteristics, essentially widening the temporal window for gender clarification. Despite promising preliminary evidence on the clinical utility of this approach, there is a dearth of research to inform evidence-based practice. In view of these challenges, we review the available empirical evidence on the cognitive, physical, and surgical implications of puberty suppression in gender-incongruent children and adolescents. We also explore the historical underpinnings and clinical impetus for suspending puberty in this population, and propose key research priorities.

Concepts: Avicenna, Gender, Gender identity, Puberty, Transgender, Third gender, Gender studies, Gonadotropin-releasing hormone agonist

1

Chronic gonadotropin-releasing hormone agonist (GnRHa) administration is used where suppression of hypothalamic-pituitary-gonadal axis activity is beneficial, such as steroid-dependent cancers, early onset gender dysphoria, central precocious puberty and as a reversible contraceptive in veterinary medicine. GnRH receptors, however, are expressed outside the reproductive axis, e.g. brain areas such as the hippocampus which is crucial for learning and memory processes. Previous work, using an ovine model, has demonstrated that long-term spatial memory is reduced in adult rams (45 weeks of age), following peripubertal blockade of GnRH signaling (GnRHa: goserelin acetate), and this was independent of the associated loss of gonadal steroid signaling. The current study investigated whether this effect is reversed after discontinuation of GnRHa-treatment. The results demonstrate that peripubertal GnRHa-treatment suppressed reproductive function in rams, which was restored after cessation of GnRHa-treatment at 44 weeks of age, as indicated by similar testes size (relative to body weight) in both GnRHa-Recovery and Control rams at 81 weeks of age. Rams in which GnRHa-treatment was discontinued (GnRHa-Recovery) had comparable spatial maze traverse times to Controls, during spatial orientation and learning assessments at 85 and 99 weeks of age. Former GnRHa-treatment altered how quickly the rams progressed beyond a specific point in the spatial maze at 83 and 99 weeks of age, and the direction of this effect depended on gonadal steroid exposure, i.e. GnRHa-Recovery rams progressed quicker during breeding season and slower during non-breeding season, compared to Controls. The long-term spatial memory performance of GnRHa-Recovery rams remained reduced (P<0.05, 1.5-fold slower) after discontinuation of GnRHa, compared to Controls. This result suggests that the time at which puberty normally occurs may represent a critical period of hippocampal plasticity. Perturbing normal hippocampal formation in this peripubertal period may also have long lasting effects on other brain areas and aspects of cognitive function.

Concepts: Brain, Hippocampus, Reproductive system, Puberty, Gonadotropin-releasing hormone, Gonadotropin-releasing hormone agonist, Precocious puberty, Histrelin