Daily Endocrinology Research Analysis
A phase 3 RCT showed that once-daily oral paltusotine rapidly normalized IGF-I and improved symptoms in uncontrolled acromegaly, with stable or reduced tumor volume. A Cochrane review reaffirmed that unopposed estrogen substantially increases endometrial hyperplasia risk, while combined estrogen–progestogen regimens mitigate it. A mechanistic study identified hypothalamic FSTL1 as a central insulin-sensitizing factor whose intranasal delivery reversed diet-induced obesity in mice via Akt–FOXO1 s
Summary
A phase 3 RCT showed that once-daily oral paltusotine rapidly normalized IGF-I and improved symptoms in uncontrolled acromegaly, with stable or reduced tumor volume. A Cochrane review reaffirmed that unopposed estrogen substantially increases endometrial hyperplasia risk, while combined estrogen–progestogen regimens mitigate it. A mechanistic study identified hypothalamic FSTL1 as a central insulin-sensitizing factor whose intranasal delivery reversed diet-induced obesity in mice via Akt–FOXO1 signaling.
Research Themes
- Oral endocrine therapeutics for pituitary disease
- Safety optimization of menopausal hormone therapy
- Central nervous system regulation of energy balance and insulin signaling
Selected Articles
1. Rapid and Sustained Response of Biochemically Uncontrolled Acromegaly to Once-Daily Oral Paltusotine Treatment.
In a 24-week, double-blind phase 3 RCT (n=111), once-daily oral paltusotine normalized IGF-I in 55.6% versus 5.3% on placebo and reduced IGF-I by −0.82×ULN, with rapid onset (within 4 weeks). GH suppression, symptom improvement, and stable or reduced pituitary tumor volume were observed, with mainly mild gastrointestinal adverse events.
Impact: This trial introduces an effective oral SSTR2 agonist that could shift acromegaly management away from injectable therapies while maintaining biochemical control and tolerability.
Clinical Implications: Paltusotine may offer a convenient oral alternative to injectable somatostatin receptor ligands for uncontrolled acromegaly, potentially improving adherence and quality of life while maintaining tumor stability.
Key Findings
- IGF-I normalization at 24 weeks: 55.6% with paltusotine vs 5.3% with placebo (P<.0001).
- Mean IGF-I change: −0.82×ULN (paltusotine) vs +0.09×ULN (placebo).
- GH (5-sample mean) <1.0 ng/mL achieved in 57.4% vs 17.5% (p<.0001).
- Acromegaly Symptom Diary improved (−2.7 vs +2.8; P=.004); tumor volume stable or reduced.
- Adverse events were mostly mild and transient gastrointestinal effects.
Methodological Strengths
- Randomized, double-blind, placebo-controlled phase 3 design with predefined strata.
- Multiple clinically relevant endpoints including IGF-I, GH, symptoms, and tumor volume.
Limitations
- 24-week duration limits assessment of long-term durability and safety.
- No head-to-head comparison with long-acting injectable SRLs; limited data in previously controlled patients after washout.
Future Directions: Head-to-head trials versus injectable SRLs, longer-term safety and tumor control data, and studies in diverse populations including treatment-experienced patients.
CONTEXT: Paltusotine is a nonpeptide, selective somatostatin receptor 2 agonist in development as once-daily oral treatment for acromegaly. OBJECTIVE: To evaluate efficacy and safety of paltusotine in patients with biochemically uncontrolled acromegaly not currently receiving medical therapy. METHODS: In this phase 3, randomized, double-blind, placebo-controlled trial, adults with medically untreated acromegaly at randomization (stratum 1: medication-naïve or off acromegaly medications ≥4 months [IGF-I ≥1.3×ULN]; stratum 2: controlled on a somatostatin receptor ligand (SRL) and underwent washout [IGF-I increase ≥30% to ≥1.1×ULN]) received paltusotine or placebo for 24 weeks. RESULTS: 111 patients (stratum 1, n=82; stratum 2, n=29) enrolled (paltusotine, n=54; placebo, n=57). The primary endpoint of IGF-I normalization at 24 weeks was met in 55.6% of paltusotine-treated patients versus 5.3% for placebo (OR: 42.81; 95% CI: 8.44-455.82; P<.0001), with superiority to placebo in both strata. Paltusotine treatment decreased IGF-I in 92.6% of patients within the first 4 weeks. All secondary endpoints were met: mean (±SE) change in IGF-I of -0.82±0.08×ULN with paltusotine versus 0.09±0.08×ULN with placebo (P<.0001); IGF-I <1.3×ULN in 66.7% versus 14.0% of patients (OR: 18.32; 95% CI: 5.64-79.16; P<.0001); GH (5-sample mean) <1.0 ng/mL in 57.4% versus 17.5% (OR: 7.59; 95% CI: 2.78-23.48; P<.0001); mean (±SE) change in Acromegaly Symptom Diary score of -2.7±1.4 versus 2.8±1.4 (P=.004). Most adverse events were acromegaly symptoms or mild, transitory gastrointestinal effects characteristic of SRLs (eg, diarrhea, abdominal pain). Pituitary tumor volume was stable or reduced in paltusotine-treated patients. CONCLUSION: IGF-I normalized in significantly more patients with uncontrolled acromegaly treated with paltusotine versus placebo. Paltusotine was associated with rapid, sustained IGF-I reduction, significant symptom improvement, and stable or reduced pituitary tumor size and was well tolerated.
2. Reversal of diet-induced obesity by central insulin sensitizer FSTL1.
Hypothalamic FSTL1, particularly in AgRP neurons, bidirectionally regulates feeding, energy expenditure, and insulin sensitivity. Intranasal FSTL1 reversed diet-induced obesity and improved insulin action in mice by interacting with Akt to restrain FOXO1 nuclear translocation.
Impact: Reveals a previously unrecognized hypothalamic pathway that sensitizes insulin signaling and reverses obesity with a translationally attractive intranasal route.
Clinical Implications: While preclinical, targeting hypothalamic FSTL1–Akt–FOXO1 signaling may offer a novel central therapy for obesity and insulin resistance; intranasal delivery could be clinically feasible pending safety and efficacy trials.
Key Findings
- FSTL1 is enriched in the hypothalamic arcuate nucleus and downregulated in DIO and db/db mice.
- AgRP neuron-specific Fstl1 deletion increases food intake, reduces energy expenditure, and impairs insulin sensitivity; overexpression produces opposite effects.
- Intranasal FSTL1 induces weight loss and improves insulin sensitivity in obese mice.
- Mechanism: FSTL1 interacts with Akt to inhibit FOXO1 nuclear translocation, requiring intact insulin signaling.
Methodological Strengths
- Complementary loss- and gain-of-function manipulations in defined neuron populations.
- Demonstration of a noninvasive intranasal therapeutic approach with mechanistic linkage to Akt–FOXO1.
Limitations
- Preclinical mouse models may not fully translate to humans; safety and off-target CNS effects are unknown.
- Duration and durability of the anti-obesity effect with chronic dosing require evaluation.
Future Directions: Define pharmacokinetics/pharmacodynamics and safety of intranasal FSTL1, assess long-term metabolic outcomes, and explore biomarkers for patient selection.
Follistatin-like 1 (FSTL1) is a signaling molecule that modulates energy metabolism in peripheral tissues and is also expressed in the brain. However, whether hypothalamic FSTL1 regulates carbohydrate/lipid metabolism and energy balance remains unknown. Here, we show that FSTL1 is enriched in the hypothalamus, especially the arcuate nucleus (ARC). FSTL1 expression is decreased in diet-induced obese (DIO) and db/db mice. Agouti-related peptide (AgRP) neuron-specific Fstl1 deletion increased food intake, decreased energy expenditure, and impaired insulin sensitivity in DIO mice. Conversely, Fstl1 overexpression in AgRP neurons resulted in the opposite phenotypes. Insulin signaling was required for the anti-obesity effect of hypothalamic FSTL1. Intranasal FSTL1 delivery promoted weight loss and improved insulin sensitivity in DIO mice. Mechanistically, FSTL1 interacts with Akt, an intracellular mediator of insulin signaling, to inhibit forkhead box protein O1 (FoxO1) nuclear translocation. Our findings identify hypothalamic FSTL1 as a key mediator counteracting DIO and provide a potential pharmacological strategy for obesity-related metabolic disorders.
3. Hormone therapy in postmenopausal women and risk of endometrial hyperplasia or endometrial cancer.
Across 72 trials (40,652 women), unopposed estrogen probably increases endometrial hyperplasia at 1 year (OR ~5.9) and after 1 year (OR ~9.0) versus placebo, and versus continuous combined regimens (OR ~22 at 1 year). Sequential combined regimens may increase 1-year hyperplasia risk versus placebo. Evidence for endometrial cancer was insufficient due to few events.
Impact: Provides high-certainty synthesis to guide safe menopausal hormone therapy by quantifying endometrial risks across regimens and durations.
Clinical Implications: Avoid unopposed estrogen in women with a uterus; prefer continuous combined estrogen–progestogen to protect the endometrium, and counsel that sequential regimens may carry higher short-term hyperplasia risk. Monitor symptoms and consider surveillance in higher-risk scenarios.
Key Findings
- Unopposed estrogen vs placebo: increased endometrial hyperplasia at 1 year (OR 5.86; moderate certainty) and after 1 year (OR 8.97; moderate certainty).
- Unopposed estrogen vs continuous combined therapy: markedly higher hyperplasia risk at 1 year (OR 21.90) and after 1 year (OR 16.78).
- Sequential combined therapy vs placebo: may increase 1-year hyperplasia risk (OR 5.53; low certainty); long-term effect less certain.
- Too few events to draw conclusions on endometrial cancer across regimens.
Methodological Strengths
- Comprehensive Cochrane methodology with RoB assessment and GRADE certainty ratings.
- Large body of randomized evidence with head-to-head and placebo comparisons.
Limitations
- Endometrial cancer outcomes were underpowered due to few events.
- Heterogeneity in regimens and doses; long-term adherence and surveillance practices varied across trials.
Future Directions: Well-powered trials and registries to assess endometrial cancer risk with modern low-dose and transdermal regimens, and optimal progestogen dosing/delivery for endometrial protection.
RATIONALE: Reduced circulating estrogen levels around the time of menopause can induce symptoms that affect health and well-being. Estrogen therapy is the most effective treatment, but may be associated with some adverse health outcomes, including endometrial pathology. This is an update of a review first published in 1999 and last updated in 2012. OBJECTIVES: • To assess the effects of hormone therapy regimens for protecting postmenopausal women against endometrial hyperplasia and endometrial cancer. • To define the lowest effective dose(s) of progestogen used in combination with estrogen therapy for protecting the endometrium. SEARCH METHODS: We searched for trials in the Cochrane Gynaecology and Fertility Group specialized register, CENTRAL (containing output from two trial registers and CINAHL), MEDLINE, Embase, and PsycINFO to 22 July 2024. We also checked references and contacted study authors to identify additional studies. ELIGIBILITY CRITERIA: Interventions of interest were unopposed estrogen, continuous combined estrogen and progestogen, and sequential combined estrogen and progestogen, administered for at least one year. These interventions could be compared head to head or with placebo. Trials had to report rates of endometrial hyperplasia or endometrial cancer (histologic diagnosis). OUTCOMES: Our critical outcomes were endometrial hyperplasia and endometrial cancer at one year and after one year. Our important outcomes were adherence to therapy, requirement for additional interventions, and withdrawal due to adverse events. RISK OF BIAS: We used the original Cochrane risk of bias tool (RoB 1). SYNTHESIS METHODS: Where meta-analysis was possible, we calculated odds ratios (ORs) with 95% confidence intervals (CIs). We used GRADE to assess the certainty of evidence for each outcome. INCLUDED STUDIES: This update included 72 studies (involving 40,652 women) conducted worldwide. There were 42 multicenter trials.