Impact of perioperative use of GnRH agonist or dienogest on ovarian reserve after cystectomy for endometriomas: a randomized controlled trial.

BACKGROUND: Ovarian endometrioma is a common gynecological disease that is often treated with surgery or hormonal treatment. Ovarian cystectomy, a surgical procedure for ovarian endometrioma, can result in impaired ovarian reserve. METHODS: We conducted a randomized controlled trial to evaluate the efficacy of hormonal treatment [gonadotropin-releasing hormone agonist (GnRHa) or dienogest (DNG)] for preserving ovarian reserve after cystectomy for ovarian endometrioma. The primary endpoint was the level of serum Anti-Müllerian hormone (AMH) as a marker of ovarian reserve. RESULTS: Before and after laparoscopic surgery, 22 patients in the GnRHa group and 27 patients in the DNG group were administered hormonal treatment for a total of 4 months. After 1-year follow-up, >60% of the patients in the DNG group retained over 70% of their pretreatment AMH levels, whereas no patient in the GnRHa group retained their AMH levels after cystectomy (P < 0.01). Interleukin-6 (IL-6) is a key cytokine involved in inflammation. Compared with the GnRHa group, patients in the DNG group had lower IL-6 levels at the end of treatment. CONCLUSIONS: Our data revealed that DNG is more effective than GnRHa in preserving ovarian reserve after cystectomy of ovarian endometrioma. This is achieved through the reduction of the inflammatory response during the perioperative period and other endometriosis-related inflammatory reactions. TRIAL REGISTRATION: The registration number of this trial is UMIN-CTR, UMIN000018569, registered 6 August 2015, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021492 , and Japan Registry of Clinical Trials, jRCTs041180140, registered 29 March 2019, https://jrct.niph.go.jp/en-latest-detail/jRCTs041180140 . This randomized controlled trial was conducted in accordance with the CONSORT guidelines.

Achieving clinically meaningful response in endometriosis pain symptoms is associated with improvements in health-related quality of life and work productivity: analysis of 2 phase III clinical trials.

BACKGROUND: Endometriosis-related pain symptoms have a negative impact on health-related quality of life and productivity. In fact, as endometriosis-related symptom severity and the number of symptoms experienced increases, health-related quality of life decreases. Dysmenorrhea and nonmenstrual pelvic pain are prominent symptoms experienced by women with endometriosis and were shown to have improved with the oral, nonpeptide gonadotropin-releasing hormone antagonist, elagolix. OBJECTIVE: The objective of this post hoc analysis was to address the question of if patients show a clinical response (in dysmenorrhea or nonmenstrual pelvic pain), do they also have improvements in health-related quality of life and in productivity? STUDY DESIGN: This post hoc analysis used data from the Elaris Endometriosis-I and Elaris Endometriosis-II phase III, randomized, placebo-controlled studies. A surgical diagnosis of endometriosis (in the past 10 years), premenopausal, aged 18-49 years, and moderate to severe endometriosis-associated pain were among the inclusion criteria for both trials. Women self-reported pain daily using a scale ranging from 0 (no pain) to 3 (severe pain); daily pain was assigned to either dysmenorrhea or nonmenstrual pelvic pain based on self-reported bleeding on that particular day. In addition, their self-reported endometriosis-associated pain must have been an average of moderate or severe during the month leading to baseline for inclusion in the trial program. Patients were characterized as achieving a clinical response for dysmenorrhea or nonmenstrual pelvic pain (ie, responder or nonresponder), which was defined as women who did not have an increase in analgesic use and who met the pain reduction score threshold at month 3. Pain reduction score thresholds were defined separately for dysmenorrhea and nonmenstrual pelvic pain in the trial using receiver-operating characteristics analysis. Health-related quality of life was assessed using the Endometriosis Health Profile-30; work productivity was assessed using the Health-Related Productivity Questionnaire. RESULTS: Women enrolled in Elaris Endometriosis-I (n = 871) and Elaris Endometriosis-II (n = 815) were included in this analysis. Patients with a clinical response during treatment to dysmenorrhea or nonmenstrual pelvic pain also experienced a meaningful improvement in all domains of the Endometriosis Health Profile-30 at month 3. Patients who did not show a dysmenorrhea or nonmenstrual pelvic pain clinical response at month 3 did not exhibit mean improvements in Endometriosis Health Profile-30 domain scores that indicate an Endometriosis Health Profile-30 responder. Productivity improved among dysmenorrhea clinical responders. In the Elaris Endometriosis-I study, clinical responders lost a total of 5.9 hours compared with a total of 13.0 hours for nonresponders of employment-related work at month 3 (P < .0001). Among women in the Elaris Endometriosis-II study, a total of 4.1 hours and 10.4 employment-related hours were lost at month 3 for dysmenorrhea responders vs nonresponders (P < .001). Similar results were obtained when analyzed by non-enstrual pelvic pain responder status. CONCLUSION: Women with moderate to severe endometriosis-related pain, who are clinical responders based on dysmenorrhea and nonmenstrual pelvic pain, also experience significant and clinically meaningful improvement in health-related quality of life and productivity as measured by the Endometriosis Health Profile-30 and Health-Related Productivity Questionnaire, respectively.

Clinical Conundrum: A 33-Year-Old With Pain Post-Orgasm and a History of Endometriosis.

A 33-year-old with a history of endometriosis presented with pain post-orgasm, accompanied by breakthrough bleeding, nausea, sweatiness, and exhaustion. History and examination suggested a gynaecologic component, likely related to the uterus itself. After several therapeutic trials, a clinical response was obtained with the use of a gonadotropin-releasing hormone antagonist, elagolix. The case is discussed with respect to dysorgasmia and post-orgasm illness syndrome. Post-orgasm pain in women has not been well studied, and it is recommended that such periorgasm phenomena be the topic of future research.

Elagolix for endometriosis: all that glitters is not gold.

Elagolix, an orally active non-peptidic GnRH antagonist, has been approved by the Food and Drug Administration for the management of moderate to severe pain associated with endometriosis. As the degree of ovarian suppression obtained with elagolix is dose-dependent, pain relief may be achieved by modulating the level of hypo-oestrogenism while limiting side effects. Elagolix may thus be considered a novelty in terms of its endocrine and pharmacological properties but not for its impact on the pathogenic mechanisms of endometriosis, as the target of this new drug is, yet again, alteration of the hormonal milieu. Given the oestrogen-dependent nature of endometriosis, a reduction of side effects may imply a proportionate decrease in pain relief. Furthermore, if low elagolix doses are used, ovulation is not consistently inhibited, and patients should use non-hormonal contraceptive systems and perform serial urine pregnancy tests to rule out unplanned conception during periods of treatment-induced amenorrhoea. If high elagolix doses are used to control severe pain for long periods of time, add-back therapies should be added, similar to that prescribed when using GnRH agonists. To date, the efficacy of elagolix has only been demonstrated in placebo-controlled explanatory trials. Pragmatic trials comparing elagolix with low-dose hormonal contraceptives and progestogens should be planned to verify the magnitude of the incremental benefit, if any, of this GnRH antagonist over currently used standard treatments. The price of elagolix may impact on patient adherence and, hence, on clinical effectiveness. In the USA, the manufacturer AbbVie Inc. priced elagolix (OrilissaTM) at around $10 000 a year, i.e. $845 per month. When faced with unaffordable treatments, some patients may choose to forego care. If national healthcare systems are funded by the tax payer, the approval and the use of a new costly drug to treat a chronic condition, such as endometriosis, means that some finite financial resources will be diverted from other areas, or that similar patients will not receive the same level of care. Thus, defining the overall 'value' of a new drug for endometriosis also has ethical implications, and trade-offs between health outcomes and costs should be carefully weighed up.

Complete remission of cerebral endometriosis with dienogest: a case report.

The most recent evidences suggest the use of progesterone mimicking drugs for the treatment of endometriosis. Particularly, dienogest has been largely tested. However, the standard treatment of extra-pelvic endometriosis is debated. Particularly, cerebral localization of endometriosis is a very rare clinical condition. The surgical approach for such a particular disorder would consist in difficult procedures, thus leading to prefer the medical treatment. We hereby report the clinical case of a cerebral localization of endometriosis treated with dienogest who experienced a complete remission of the disease.

Infertility secondary to a pituitary adenoma.

Evaluating patients for infertility is common in the primary care setting and can involve multiple differentials and treatment options. This case report describes a 34-year-old woman whose infertility evaluation led to the diagnosis of a pituitary adenoma.

Unscheduled vaginal bleeding with progestin-only contraceptive use.

Nearly 20% of women using contraception are using progestin-only contraception, including progestin-only pills, depot-medroxyprogesterone acetate, subdermal etonogestrel implants, and levonorgestrel intrauterine devices. This number will continue to grow with the increased provision of long-acting reversible contraception. Although overall satisfaction among women using progestin-only contraception is high, dissatisfaction and discontinuation may be associated with unscheduled bleeding and spotting. The exact etiology of irregular bleeding associated with progestin-containing contraceptives is not completely understood, yet several mechanisms have been suggested. Several therapies targeting these mechanisms have been evaluated with mixed results. This paper will review the physiology and management of unscheduled bleeding with progestin-containing contraceptives.

An Evidence-based Approach to the Medical Management of Fibroids: A Systematic Review.

Fibroids are the most common tumor of the female reproductive tract, but approved medical treatments are limited. Patients demand uterine-sparing treatments which preserve fertility and avoid surgery. We systematically reviewed PubMed and Cochrane databases from January 1985 to November 2015 for evidence-based medical therapies for fibroids in the context of disease prevention, treatment of early disease, treatment of symptomatic disease, and preoperative management. We identified 2182 studies, of which 52 studies met inclusion and exclusion criteria. Published data affirm the efficacy of multiple agents, which are promising avenues for the development of medical alternatives to surgery.

Medical combination therapies in Cushing's disease.

INTRODUCTION: There has been growing interest on medical therapy for the management of Cushing's disease (CD), particularly in cases of persistent or recurrent hypercortisolism. Ketoconazole, an inhibitor of adrenal steroidogenesis, is the most widely used drug, whereas cabergoline and pasireotide are the most promising centrally acting agents. The main purpose of this review article is to highlight the options of medical treatment for CD, with a special emphasis on combination therapies, a topic that has only been addressed by a limited number of studies. CONCLUSIONS: According to the results of these studies, combination therapies involving medications with additive or synergistic effects on ACTH and cortisol secretion seem quite attractive as they yield higher probability of longterm control of the hypercortisolism at lower doses, a lower incidence of side-effects, and possibly a lower rate of treatment escapes. Currently, ketoconazole, cabergoline, and pasireotide are the best drugs to be prescribed in combination.

Medical therapy for Cushing's disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers.

Morbidity and mortality in Cushing's disease (CD) patients are increased if patients are not appropriately treated. Surgery remains the first line therapy, however the role of medical therapy has become more prominent in patients when biochemical remission is not achieved/or recurs after surgery, while waiting effects of radiation therapy or when surgery is contraindicated. Furthermore, use of preoperative medical therapy has been also recognized. In addition to centrally acting therapies (reviewed elsewhere in this special issue), adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are frequently used. A PubMed search of all original articles or abstracts detailing medical therapy in CD, published within 12 months (2013-2014), were identified and pertinent data extracted. Although not prospectively studied, ketoconazole and metyrapone have been the most frequently used medical therapies. A large retrospective ketoconazole study showed that almost half of patients who continued on ketoconazole therapy achieved biochemical control and clinical improvement; however almost 20% discontinued ketoconazole due to poor tolerability. Notably, hepatotoxicity was usually mild and resolved after drug withdrawal. Etomidate remains the only drug available for intravenous use. A new potent inhibitor of both aldosterone synthase and 11ß-hydroxylase, following the completion of a phase II study LCI699 is being studied in a large phase III with promising results. Mifepristone, a glucocorticoid receptor antagonist, has been approved for hyperglycemia associated with Cushing's syndrome based on the results of a prospective study where it produced in the majority of patients' significant clinical and metabolic improvement. Absence of both a biochemical marker for remission and/or diagnosis of adrenal insufficiency remain, however, a limiting factor. Patient characteristics and preference should guide the choice between different medications in the absence of clinical trials comparing any of these therapies. Despite significant progress, there is still a need for a medical therapy that is more effective and with less adverse effects for patients with CD.

Dienogest in the treatment of endometriosis: systematic review.

PURPOSE: Endometriosis is a prevalent disease that affects 5-15 % of women of reproductive age. The aim of this study is to assess the effect of dienogest in the treatment of endometriosis. METHODS: The search was applied to electronic databases PubMed, Cochrane, EMBASE and Lilacs until September 2014, in a public tertiary hospital. We performed a systematic literature search of randomized trials comparing dienogest to other medical therapies in the treatment of endometriosis, as well as their references list, using the keywords "dienogest" and "endometriosis" by two independent authors. The data extraction were performed by two authors using predefined data fields. Nine randomized trials were included. Dienogest 2 mg/day was superior to placebo in reducing pelvic pain (27.4 versus 15.1 mm, P < 0.0001), with similar results to buserelin, leuprorelin, leuprolide acetate and triptorelin, in controlling symptoms associated with endometriosis. Dienogest 2 mg/day was effective in reducing endometriotic lesions (11.4 ± 1.71-3.6 ± 0.95, P < 0.001). The extended therapy with dienogest 2 mg/day also showed an improvement in pelvic pain after 24-52 weeks (-22.5 ± 32.1 and -28.4 ± 29.9 mm, respectively) with tolerable side effects. CONCLUSION: Dienogest should be considered as an alternative for controlling symptoms related to endometriosis. Nevertheless, in this systematic review, no studies were found comparing dienogest with first-line therapy, such as progestins and estrogen-progestogen combinations, which are proved to be effective in the treatment of endometriosis, are less expensive, and also can be used for contraception.

Relief of uterine bleeding by cyclic administration of dienogest for endometriosis.

OBJECTIVE: This study assessed the relief of uterine bleeding and clinical symptoms during cyclic administration of dienogest for the treatment of endometriosis. METHODS: In total, 25 patients undergoing ovarian cyst enucleation and given dienogest participated in this study. Dienogest 2 mg/day was administered for 3 weeks, and the drug was then withdrawn for 1 week (cyclic administration of dienogest). This 4-week cycle was repeated six times. Patients' records were prospectively analyzed for the number of days on which any uterine bleeding occurred, as well as menstrual pain before and after the start of dienogest administration were evaluated with a view to using the data obtained herein as the basis. RESULTS: During the period of cyclic administration of dienogest, uterine bleeding occurred on 5.8 to 7.7 days per 4-week period on an average through cycles. Of uterine bleeding episodes, menstruation-like uterine bleeding was present in about 80% of patients. The visual analog scale (VAS) value for menstrual pain significantly decreased from 3.8 before dienogest administration after surgery to 1.5 at the completion of cycle 1, VAS remained low thereafter. CONCLUSION: These results raise the possibility that cyclic administration of dienogest may relieve lessen uterine bleeding, a major adverse event and menstrual pain.

Efficacy and safety of dienogest in the treatment of deep infiltrating endometriosis: A meta-analysis.

OBJECTIVE: To systematically review and conduct a meta-analysis to assess the effectiveness of dienogest (DNG) in the prolonged conservative drug management of deep infiltrating endometriosis (DIE). The findings from this study are intended to serve as a valuable reference for clinical decision-making regarding medication in the context of DIE. METHODS: Following the PRISMA Statement, we searched EMBASE, PubMed, The Cochrane Library, Web of Science, and Medline databases for relevant literature published in the public domain from the date of establishment of the database until October 2023. Subsequently, all English publications on clinical studies using DNG for the treatment of DIE were included. Studies involving surgical intervention or drug therapy for postoperative recurrence were excluded. All literature included in the review underwent risk assessment of bias. Two evaluators independently screened the publications, conducted a quality assessment of each article and extracted data. We used Revman 5.4 for the meta-analysis of the included literature. RESULTS: Our final analysis consisted of five clinical studies, involving a total of 256 patients. We found that there were significant improvements in the following indicators post-medication as compared to levels before taking the medication: dysmenorrhea (MD = 4.24, 95 % CI: 2.92-5.56, P < 0.00001), non-menstrual pelvic pain (MD = 3.11, 95 % CI: 2.34-3.88, P < 0.00001), dyspareunia (MD = 1.93, 95 % CI: 1.50-2.37, P < 0.00001), dyschezia (MD = 2.48, 95 % CI: 1.83-3.12, P < 0.00001), and rectosigmoid nodule size (MD = 0.32, 95 % CI: 0.18-0.46, P < 0.00001). Compared with pre-medication levels, the following indicators were significantly worse: headache (RR = 0.03, 95 % CI: 0.00-0.23, P = 0.0006), decreased libido (RR = 0.08, 95 % CI: 0.01-0.62, P = 0.02); and there was no significant improvement in dysuria (P > 0.05). CONCLUSION: DNG showed efficacy in relieving pain-related symptoms and significantly reducing the size of the lesions when used in the drug conservative treatment of DIE.

Where vaptans do and do not fit in the treatment of hyponatremia.

The treatment of hyponatremia, an exceedingly common electrolyte disorder, has been a subject of controversy for many years. The advent of vasopressin antagonists (vaptans) has added to the treatment arsenal. This review focuses on why hyponatremia should be treated and the role of these antagonists in the treatment. Upon analysis of the available literature, we conclude that there is presently no role for vaptans in acute symptomatic hyponatremia. Although numerous therapeutic approaches are available for chronic symptomatic hyponatremia, vasopressin antagonists provide a simpler treatment option. Vaptans are efficacious in raising serum sodium in long-standing 'asymptomatic' hyponatremia. However, the cost of the only Food and Drug Administration-approved oral agent (tolvaptan) makes its use prohibitive for most patients in this setting.

Effect of Mifepristone vs Placebo for Treatment of Adenomyosis With Pain Symptoms: A Randomized Clinical Trial.

Importance: Adenomyosis is a common chronic gynecological disorder, and its treatment is an unmet need. New therapies need to be developed. Mifepristone is being tested for adenomyosis treatment. Objective: To determine whether mifepristone is effective and safe for adenomyosis treatment. Design, Setting, and Participants: This multicenter, placebo-controlled, double-blind randomized clinical trial was conducted in 10 hospitals in China. In total, 134 patients with adenomyosis pain symptoms were enrolled. Trial enrollment began in May 2018 and was completed in April 2019, and analyses were conducted from October 2019 to February 2020. Interventions: Participants were randomized 1:1 to receive mifepristone 10 mg or placebo orally once a day for 12 weeks. Main Outcomes and Measures: The primary end point was the change in adenomyosis-associated dysmenorrhea intensity, evaluated by the visual analog scale (VAS) after 12 weeks of treatment. Secondary end points included the change in menstrual blood loss, increased level of hemoglobin in patients with anemia, CA125 level, platelet count, and uterine volume after 12 weeks of treatment. Safety was assessed according to adverse events, vital signs, gynecological examinations, and laboratory evaluations. Results: In total, 134 patients with adenomyosis and dysmenorrhea were randomly assigned, and 126 patients were included in the efficacy analysis, including 61 patients (mean [SD] age, 40.2 [4.6] years) randomized to receive mifepristone and 65 patients (mean [SD] age, 41.7 [5.0] years) randomized to received the placebo. The characteristics of the included patients at baseline were similar between groups. The mean (SD) change in VAS score was -6.63 (1.92) in the mifepristone group and -0.95 (1.75) in the placebo group (P < .001). The total remission rates for dysmenorrhea in the mifepristone group were significantly better than those in the placebo group (effective remission: 56 patients [91.8%] vs 15 patients [23.1%]; complete remission: 54 patients [88.5%] vs 4 patients [6.2%]). All the secondary end points showed significant improvements after mifepristone treatment for menstrual blood loss, hemoglobin (mean [SD] change from baseline: 2.13 [1.38] g/dL vs 0.48 [0.97] g/dL; P < .001), CA125 (mean [SD] change from baseline: -62.23 [76.99] U/mL vs 26.89 [118.70] U/mL; P < .001), platelet count (mean [SD] change from baseline: -28.87 [54.30]×103/µL vs 2.06 [41.78]×103/µL; P < .001), and uterine volume (mean [SD] change from baseline: -29.32 [39.34] cm3 vs 18.39 [66.46] cm3; P < .001). Safety analysis revealed no significant difference between groups, and no serious adverse events were reported. Conclusions and Relevance: This randomized clinical trial showed that mifepristone could be a new option for treating patients with adenomyosis, based on its efficacy and acceptable tolerability. Trial Registration: ClinicalTrials.gov Identifier: NCT03520439.

Treatment of endometriosis in different ethnic populations: a meta-analysis of two clinical trials.

Approaches to the treatment of endometriosis vary worldwide, but studies comparing endometriosis medications in different ethnic groups are rare. A systematic literature search identified two studies directly comparing dienogest (DNG) versus gonadotropin-releasing hormone (GnRH) analogues in European and Japanese populations. Meta-analysis of visual analogue scale scores revealed no heterogeneity in response between the trials, indicating equivalent efficacy of DNG and GnRH analogues for endometriosis-related pain across populations. DNG was significantly superior to GnRH analogues for bone mineral density change in both trials, but significant heterogeneity between the studies may indicate ethnic differences in physiology.

Oxytocin antagonists for the management of preterm birth: a review.

Preterm birth, the leading cause of neonatal morbidity and mortality, is estimated at incidence of 12.7% of all births, which has not decreased over the last four decades despite intensive antenatal care programs aimed at high-risk groups, the widespread use of tocolytics, and a series of other preventive and therapeutic interventions. Oxytocin antagonists, namely atosiban, represent an appealing choice that seems to be effective with apparently fewer side effects than the traditional tocolytics. This article reviews the available literature on the pharmacokinetics, mode of administration, and clinical utility of oxytocin antagonists for acute and maintenance tocolysis with special emphasis on its safety profile.

Pregnancy associated with recurrent acromegaly: a case report.

BACKGROUND: Acromegaly is an uncommon endocrine disorder. Pregnancy is an unusual event in acromegalic females because fertility is often reduced. With the advent of advanced surgical and medical management, more acromegalic women will achieve pregnancy. Reports of pregnancy in acromegaly and recurrent acromegaly postpartum are rare. OBJECTIVE: To present a rare occurrence of pregnancy in acromegaly after macroadenectomy and recurrent acromegaly postpartum. METHODS: Clinical and biochemical evaluation of a 39-year-old female Nigerian with features of acromegaly before and after macroadenectomy and postpartum was done. Investigations carried out included oral glucose tolerance test with serial growth hormone assays and insulin-like growth factor 1 as well as computed tomography scan and magnetic resonance imaging of the pituitary. RESULTS: There was a history of menorrhagia, swelling of the feet and increasing coarsening of the facial appearance. She had biochemical evidence of acromegaly and subsequently had a transsphenoidal macroadenectomy. There was postoperative clinical and biochemical remission. Magnetic resonance imaging done six months postsurgery showed no evidence of tumour regrowth. Clinical and biochemical evidence of acromegaly recurred after pregnancy. Magnetic resonance imaging confirmed tumour regrowth. CONCLUSION: Pregnancy in treated acromegaly, though a rare occurrence, is achievable but is capable of provoking recurrence of acromegaly.

Baseline cortisol and the efficacy of antiglucocorticoid treatment in mood disorders: A meta-analysis.

INTRODUCTION: Hyperactivity of the Hypothalamic-Pituitary-Adrenal (HPA) axis and high cortisol levels have been widely reported in patients with mood disorders but previous clinical trials investigating the efficacy of antiglucocorticoid treatment in this population have reported inconsistent findings. The inconsistencies among these studies may be because not all patients with mood disorders have increased HPA axis activity and therefore might not benefit from antiglucocorticoid treatment. The aim of this meta-analysis was to investigate whether baseline cortisol levels influence the efficacy of antiglucocorticoid drugs in patients with mood disorders. METHODS: PubMed and Scopus databases were searched systematically up to October 2018. We included studies using metyrapone, ketoconazole or mifepristone in patients with major depressive disorder, bipolar disorder and major depressive disorder with psychotic symptoms. We tested for a difference in cortisol levels between responders (a reduction equal to or greater than 30% on depression scales following antiglucocorticoid treatment) and non-responders (a reduction of less than 30% on depression scales). We performed a meta-analysis to look specifically at differences in cortisol levels in the sample of patients treated with cortisol synthesis inhibitors (metyrapone and ketoconazole) and in those treated with glucocorticoid receptor (GR) antagonist (mifepristone). RESULTS: We were able to retrieve data from 11 of the 16 selected studies and to include 9 studies in the meta-analysis. In the overall sample (N = 846), responders had similar baseline cortisol levels compared with non-responders (standardised mean difference, SMD = -0.03, 95% CI [-0.17, 0.12], p = 0.75). In the group of patients treated with cortisol synthesis inhibitors, responders (N = 109) had significantly higher peripheral baseline cortisol levels compared with non-responders (SMD = 0.42, 95% CI [0.01, 0.83], p = 0.047). In the group of patients treated with a GR antagonist (N = 737), both responders and non-responders had similar baseline cortisol levels (SMD = -0.09, 95% CI [-0.25, 0.07], p = 0.26). CONCLUSION: Our data suggest that only patients with higher cortisol levels at baseline benefit from treatment with cortisol synthesis inhibitors and support a potential role for cortisol as a predictive biomarker for treatment with cortisol synthesis inhibitors in patients with mood disorders.

Plasma Agouti-Related Protein Levels in Acromegaly and Effects of Surgical or Pegvisomant Therapy.

CONTEXT: GH activates agouti-related protein (AgRP) neurons, leading to orexigenic responses in mice. The relationship between serum GH and plasma AgRP, which has been shown to reflect hypothalamic AgRP, has not been evaluated in humans. OBJECTIVE: To test the hypothesis that central stimulatory actions of GH on hypothalamic AgRP could be reflected in plasma AgRP in acromegaly. METHODS: We studied 23 patients with active acromegaly before and for ≤2 years after surgical (n = 13) or GH receptor antagonist therapy with pegvisomant (n = 10), and 100 healthy subjects with morning fasting blood samples for AgRP, leptin, GH, and IGF-1 and anthropometric measurements. RESULTS: The plasma AgRP levels were higher in those with active acromegaly than in the matched healthy subjects [median, 100 pg/mL; interquartile range (IQR), 78 to 139 pg/mL vs median, 63 pg/mL; IQR, 58 to 67 pg/mL; P < 0.0001]. Plasma AgRP decreased from before to after surgery (median, 102 pg/mL; IQR, 82 to 124 pg/mL vs median, 63 pg/mL; IQR, 55.6 to 83 pg/mL; P = 0.0024) and from before to during pegvisomant therapy (median, 97 pg/mL; IQR, 77 to 175 pg/mL vs median, 63; IQR, 61 to 109 pg/mL; P = 0.006). The plasma AgRP level correlated with GH (r = 0.319; P = 0.011) and IGF-1 (r = 0.292; P = 0.002). In repeated measure analysis, AgRP was significantly associated with IGF-1. CONCLUSIONS: Our data have provided evidence of a stimulatory effect of GH on plasma AgRP in humans. The levels were greater in active acromegaly and decreased in parallel with GH and IGF-1 decreases with acromegaly treatment. Data from mice suggest that AgRP may mediate some of the known effects of GH on energy metabolism. This warrants further study in patients with acromegaly and other populations.