Background: Growth hormone has been used as an adjunct in ovarian stimulation of IVF cycles for the past three decades. However, the exact mechanism of its role in improving oocyte quality has not been thoroughly investigated. Although a clear indication for GH co-treatment is in infertile women with GH deficiency, GH has been given mostly to poor ovarian responders. Method: This paper is a review of the most recent published data on the role of GH supplementation in improving oocyte quality in younger women who are suboptimal or unexpected poor responders to standard ovarian stimulation. Results: Retrospective cohort and randomized trials demonstrated an improvement in oocyte quality through morphological parameters, mitochondrial function, biomarkers, GH receptors, insulin growth factor, markers of oxidative stress, mature oocytes, good quality embryos, implantation rate, clinical pregnancy and live birth. Conclusion Current data suggest GH supplementation may improve oocyte and embryo qualities, endometrial receptivity, clinical pregnancy and live birth. However, better quality evidence is needed before a recommendation can be made for GH supplementation to be given to infertile women who are suboptimal or poor ovarian responders.
growth hormone ; hormone receptor ; IGF-1 ; IVF

OBJECTIVE: To explore the effect of curcumin on the insulin receptor substrate 1 (IRS1)/phosphatidylinositol-3-kinase (PI3K)/endometrial expression of glucose 4 (GLUT4) signalling pathway and its regulator, phosphatase and tensin homolog (PTEN), in a rat model of polycystic ovarian syndrome (PCOS). METHODS: PCOS model was induced by letrozole intragastric administration. Sprague-Dawley rats were randomized into 4 groups according to a random number table: (1) control group; (2) PCOS group, which was subjected to PCOS and received vehicle; (3) curcumin group, which was subjected to PCOS and treated with curcumin (200 mg/kg for 2 weeks); and (4) curcumin+LY294002 group, which was subjected to PCOS, and treated with curcumin and LY294002 (a specific PI3K inhibitor). Serum hormone levels (17 β-estradiol, follicle stimulating hormone, luteinizing hormone, progesterone, and testosterone) were measured by enzyme linked immunosorbent assay, and insulin resistance (IR) was assessed using the homeostasis model assessment of IR. Ovarian tissues were stained with haematoxylin and eosin for pathological and apoptosis examination. Expression levels of key transcriptional regulators and downstream targets, including IRS1, PI3K, protein kinase B (AKT), GLUT4, and PTEN, were measured via reverse transcription polymerase chain reaction and Western blot, respectively. RESULTS: The PCOS group showed impaired ovarian morphology and function. Compared with the PCOS group, curcumin treatment exerted ovarioprotective effects, down-regulated serum testosterone, restored IR, inhibited inflammatory cell infiltration in ovarian tissues, decreased IRS1, PI3K, and AKT expressions, and up-regulated GLUT4 and PTEN expressions in PCOS rats (P<0.05 or P<0.01). In contrast, IRS1, PI3K, AKT, and PTEN expression levels were not significantly different between PCOS and curcumin+LY294002 groups (P>0.05). CONCLUSION The beneficial effects of curcumin on PCOS rats included the alteration of serum hormone levels and recovery of morphological ovarian lesions, in which, PTEN, a new target, may play a role in regulating the IRS1/PI3K/GLUT4 pathway.
Animals ; Female ; Humans ; Rats ; Cell Proliferation ; Curcumin/therapeutic use* ; Follicle Stimulating Hormone ; Glucose ; Hyperandrogenism ; Insulin Receptor Substrate Proteins/metabolism* ; Insulin Resistance ; Ovarian Cysts ; Ovarian Neoplasms ; Phosphatidylinositol 3-Kinase/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Polycystic Ovary Syndrome/drug therapy* ; Proto-Oncogene Proteins c-akt/metabolism* ; Rats, Sprague-Dawley ; Testosterone

Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases SUMMARY Programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) have been widely used in lung cancer treatment, but their immune-related adverse events (irAEs) require intensive attention. Pituitary irAEs, including hypophysitis and hypopituitarism, are commonly induced by cytotoxic T lymphocyte antigen 4 inhibitors, but rarely by PD-1/PD-L1 inhibitors. Isolated adrenocorticotropic hormone(ACTH) deficiency (IAD) is a special subtype of pituitary irAEs, without any other pituitary hormone dysfunction, and with no enlargement of pituitary gland, either. Here, we described three patients with advanced lung cancer who developed IAD and other irAEs, after PD-1 inhibitor treatment. Case 1 was a 68-year-old male diagnosed with metastatic lung adenocarcinoma with high expression of PD-L1. He was treated with pembrolizumab monotherapy, and developed immune-related hepatitis, which was cured by high-dose methylprednisolone [0.5-1.0 mg/(kg·d)]. Eleven months later, the patient was diagnosed with primary gastric adenocarcinoma, and was treated with apatinib, in addition to pembrolizumab. After 17 doses of pembrolizumab, he developed severe nausea and asthenia, when methylprednisolone had been stopped for 10 months. His blood tests showed severe hyponatremia (121 mmol/L, reference 137-147 mmol/L, the same below), low levels of 8:00 a.m. cortisol (< 1 μg/dL, reference 5-25 μg/dL, the same below) and ACTH (2.2 ng/L, reference 7.2-63.3 ng/L, the same below), and normal thyroid function, sex hormone and prolactin. Meanwhile, both his lung cancer and gastric cancer remained under good control. Case 2 was a 66-year-old male with metastatic lung adenocarcinoma, who was treated with a new PD-1 inhibitor, HX008, combined with chemotherapy (clinical trial number: CTR20202387). After 5 months of treatment (7 doses in total), his cancer exhibited partial response, but his nausea and vomiting suddenly exacerbated, with mild dyspnea and weakness in his lower limbs. His blood tests showed mild hyponatremia (135 mmol/L), low levels of 8:00 a.m. cortisol (4.3 μg/dL) and ACTH (1.5 ng/L), and normal thyroid function. His thoracic computed tomography revealed moderate immune-related pneumonitis simultaneously. Case 3 was a 63-year-old male with locally advanced squamous cell carcinoma. He was treated with first-line sintilimab combined with chemotherapy, which resulted in partial response, with mild immune-related rash. His cancer progressed after 5 cycles of treatment, and sintilimab was discontinued. Six months later, he developed asymptomatic hypoadrenocorticism, with low level of cortisol (1.5 μg/dL) at 8:00 a.m. and unresponsive ACTH (8.0 ng/L). After being rechallenged with another PD-1 inhibitor, teslelizumab, combined with chemotherapy, he had pulmonary infection, persistent low-grade fever, moderate asthenia, and severe hyponatremia (116 mmol/L). Meanwhile, his blood levels of 8:00 a.m. cortisol and ACTH were 3.1 μg/dL and 7.2 ng/L, respectively, with normal thyroid function, sex hormone and prolactin. All of the three patients had no headache or visual disturbance. Their pituitary magnetic resonance image showed no pituitary enlargement or stalk thickening, and no dynamic changes. They were all on hormone replacement therapy (HRT) with prednisone (2.5-5.0 mg/d), and resumed the PD-1 inhibitor treatment when symptoms relieved. In particular, Case 2 started with high-dose prednisone [1 mg/(kg·d)] because of simultaneous immune-related pneumonitis, and then tapered it to the HRT dose. His cortisol and ACTH levels returned to and stayed normal. However, the other two patients' hypopituitarism did not recover. In summary, these cases demonstrated that the pituitary irAEs induced by PD-1 inhibitors could present as IAD, with a large time span of onset, non-specific clinical presentation, and different recovery patterns. Clinicians should monitor patients' pituitary hormone regularly, during and at least 6 months after PD-1 inhibitor treatment, especially in patients with good oncological response to the treatment.
Adenocarcinoma of Lung/drug therapy* ; Adrenocorticotropic Hormone/therapeutic use* ; Aged ; B7-H1 Antigen/therapeutic use* ; Humans ; Hydrocortisone/therapeutic use* ; Hyponatremia/drug therapy* ; Hypopituitarism/drug therapy* ; Immune Checkpoint Inhibitors ; Lung Neoplasms/pathology* ; Male ; Methylprednisolone/therapeutic use* ; Middle Aged ; Nausea/drug therapy* ; Pituitary Gland/pathology* ; Pneumonia ; Prednisone/therapeutic use* ; Programmed Cell Death 1 Receptor/therapeutic use* ; Prolactin/therapeutic use*

Osteoporosis is a skeletal disorder characterized by compromised bone strength resulting in a predisposition to fracture. Osteoporosis-related fractures can lead to pain, disability, and increased healthcare costs. This study aimed to explore different pharmacological treatments for osteoporosis. Various treatments are used to prevent and treat osteoporosis, particularly in postmenopausal women and elderly men, but the approach needs to be individually tailored. Bisphosphonates are most commonly used to treat osteoporosis. Bisphosphonates and denosumab are mainly used during the initial phase of therapy for most patients with osteoporosis, including those with a high risk of fracture. In younger postmenopausal women, menopausal hormone therapy (including tibolone) and selective estrogen receptor modulators may be considered as alternatives for fracture prevention. Parathyroid hormone therapy is recommended for osteoporosis treatment in elderly patients with an increased risk of multiple vertebral fractures. Dual energy X-ray absorptiometry (DXA) is the mainstay for monitoring the treatment response, and clinicians may consider alternative treatments if a significant decrease in bone mineral density is detected (using DXA or bone turnover markers) or if recurrent fractures occur during treatment. For postmenopausal women undergoing long-term bisphosphonate treatment, the risk of fracture should be reassessed after 3 to 5 years, and a “drug holiday” should be considered if the risk of fracture is low-to-moderate. Therapy should be continued for patients who continue to exhibit a high risk of fracture, or alternatively, switching to other treatments may be considered.
Absorptiometry, Photon ; Aged ; Bone Density ; Bone Remodeling ; Denosumab ; Diphosphonates ; Drug Therapy ; Female ; Health Care Costs ; Humans ; Male ; Osteoporosis ; Parathyroid Hormone ; Selective Estrogen Receptor Modulators

Drynariae Rhizoma has great significance in the clinical practice of osteoporosis treatment. Based on the perspective of integrative pharmacology, the study explored the mechanism of action of Drynariae Rhizoma in the treatment of osteoporosis. Six active components in Drynariae Rhizoma were obtained, mainly including glycosides and sterols. Taking the median of 2 times of "node connectivity" as the card value, the core node of the Chinese medicine target disease gene interaction network was selected. Based on this, three topological structural eigenvalues, such as "node connectivity" "node tightness" and "node connectivity" were calculated, thereby screening out four core targets of Drynariae Rhizoma treatment for osteoporosis, including thyroid parathyroid hormone 1 receptor (PTH1R), parathyroid hormone 2 receptor (PTH2R), calcitonin receptor gene (CALCR), and SPTBN1 gene (SPTBN1). Based on the gene ontology database GO and KEGG pathway database, the molecular function, intracellular localization, and biological reactions and pathways of proteins encoded by drug target genes were determined. Combined with enrichment calculation, it is predicted that osteoporosis may play a role in biosynthetic processes, such as circulatory system, nervous system, energy metabolism, prolactin signal pathway, GnRH signaling pathway, neurotrophic factor signaling pathway and other pathway. The conclusion of this study is certain with the existing research results, and the new target and new pathway could also be used as a theoretical basis for the further verification of osteoporosis.
Drugs, Chinese Herbal ; pharmacology ; Humans ; Osteoporosis ; drug therapy ; Polypodiaceae ; chemistry ; Receptor, Parathyroid Hormone, Type 1 ; metabolism ; Receptor, Parathyroid Hormone, Type 2 ; metabolism ; Receptors, Calcitonin ; metabolism ; Rhizome ; chemistry ; Spectrin ; metabolism

Hyponatremia is a commonly observed complication that is related to hypoalbuminemia and portal hypertension in patients with advanced liver cirrhosis. Hyponatremia in patients with liver cirrhosis is mostly dilutional hyponatremia and is defined when the serum sodium concentration is below 130 meq/L. The risk of complications increases significantly in cirrhotic patients with hyponatremia, which includes spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. In addition, hyponatremia is associated with increased morbidity and mortality in patients with cirrhosis, and is an important prognostic factor before and after liver transplantation. The conventional therapies of hyponatremia are albumin infusion, fluid restriction and loop diuretics, but these are frequently ineffective. This review investigates the pathophysiology and various therapeutic modalities, including selective vasopressin receptor antagonists, for the management of hyponatremia in patients with liver cirrhosis.
Antidiuretic Hormone Receptor Antagonists ; Fibrosis ; Hepatic Encephalopathy ; Hepatorenal Syndrome ; Humans ; Hypertension, Portal ; Hypoalbuminemia ; Hyponatremia* ; Liver Cirrhosis* ; Liver Transplantation ; Liver* ; Mortality ; Peritonitis ; Sodium ; Sodium Potassium Chloride Symporter Inhibitors

PURPOSE: Zinc (Zn) is an essential trace element for bone mineralization and osteoblast function. We examined the effects of Zn deficiency on osteoblast differentiation and mineralization in MC3T3-E1 cells. METHODS: Osteoblastic MC3T3-E1 cells were cultured at concentration of 1 to 15 µM ZnCl2 (Zn− or Zn+) for 5, 15 and 25 days up to the calcification period. Extracellular matrix mineralization was detected by staining Ca and P deposits using Alizarin Red and von Kossa stain respectively, and alkaline phosphatase (ALP) activity was detected by ALP staining and colorimetric method. RESULTS: Extracellular matrix mineralization was decreased in Zn deficiency over 5, 15, and 25 days. Similarly, staining of ALP activity as the sign of an osteoblast differentiation, was also decreased by Zn deficiency over the same period. Interestingly, the gene expression of bone-related markers (ALP, PTHR; parathyroid hormone receptor, OPN; osteopontin, OC; osteocalcin and COLI; collagen type I), and bone-specific transcription factor Runx2 were downregulated by Zn deficiency for 5 or 15 days, however, this was restored at 25 days. CONCLUSION: Our data suggests that Zn deficiency inhibits osteoblast differentiation by retarding bone marker gene expression and also inhibits bone mineralization by decreasing Ca/P deposition as well as ALP activity.
Alkaline Phosphatase ; Calcification, Physiologic ; Collagen ; Extracellular Matrix ; Gene Expression* ; Methods ; Miners* ; Osteoblasts* ; Osteocalcin ; Osteopontin ; Receptor, Parathyroid Hormone, Type 1 ; Transcription Factors ; Zinc*

PURPOSE: Although combining aromatase inhibitors (AI) with gonadotropin-releasing hormone agonists (GnRHa) is becoming more common, it is still not clear if GnRHa is as effective as bilateral salpingo-oophorectomy (BSO). MATERIALS AND METHODS: We retrospectively analyzed data of 66 premenopausal patients with hormone receptor– positive, human epidermal growth factor receptor 2–negative recurrent and metastatic breast cancer who had been treated with AIs in combination with GnRHa or BSO between 2002 and 2015. RESULTS: The median patient age was 44 years. Overall, 24 (36%) received BSO and 42 (64%) received GnRHa. The clinical benefit rate was higher in the BSO group than in the GnRHa group (88% vs. 69%, p=0.092). Median progression-free survival (PFS) was longer in the BSO group, although statistical significance was not reached (17.2 months vs. 13.3 months, p=0.245). When propensity score matching was performed, the median PFS was 17.2 months for the BSO group and 8.2 months for the GnRHa group (p=0.137). Multivariate analyses revealed that the luminal B subtype (hazard ratio, 1.67; 95% confidence interval [CI], 1.08 to 2.60; p=0.022) and later-line treatment (≥ third line vs. first line; hazard ratio, 3.24; 95% CI, 1.59 to 6.59; p=0.001) were independent predictive factors for a shorter PFS. Incomplete ovarian suppression was observed in a subset of GnRHa-treated patients whose disease showed progression, with E2 levels higher than 21 pg/mL. CONCLUSION: Both BSO and GnRHa were found to be effective in our AI-treated premenopausal metastatic breast cancer patient cohort. However, further studies in larger populations are needed to determine if BSO is superior to GnRHa.
Aromatase Inhibitors* ; Aromatase* ; Breast Neoplasms* ; Breast* ; Cohort Studies ; Disease-Free Survival ; Female ; Gonadotropin-Releasing Hormone* ; Humans ; Multivariate Analysis ; Ovariectomy ; Phenobarbital ; Premenopause ; Propensity Score ; Receptor, Epidermal Growth Factor ; Retrospective Studies

Historically, endocrine therapy for breast cancer began with ovarian ablation (OA) for the treatment of premenopausal patients. After the identification of estrogen receptors and the development of many antiestrogens, tamoxifen has been approved and used as the standard endocrine therapy for hormonal receptor (HR)-positive premenopausal patients to date. With the development of luteinizing hormone-releasing hormone agonists, the paradigm of endocrine therapy for premenopausal women with HR-positive breast cancer began to change from OA to ovarian function suppression (OFS). To date, the indication for OFS was limited to those premenopausal patients with HR-positive breast cancer who were unable to use tamoxifen as the primary adjuvant endocrine therapy. However, following the definitive demonstration of the therapeutic role of OFS added to tamoxifen or aromatase inhibitor after chemotherapy in large randomized trials, such as Tamoxifen and Exemestane Trial or Suppression of Ovarian Function Trial, the American Society of Clinical Oncology guidelines for the use of endocrine therapy in premenopausal HR-positive breast cancer were recently updated to recommend OFS in high-risk patients who required adjuvant chemotherapy. In contrast, the role of OFS to protect ovarian function during chemotherapy in premenopausal women has remained controversial, and some evidence showing the protective effect of OFS on the ovaries during chemotherapy as well as its therapeutic effect for breast cancer in premenopausal women with HR-negative breast cancer was recently published. Further evaluation is necessary to determine its exact role. In conclusion, the role of OA or OFS has been evolving, not only to improve the efficacy of breast cancer treatment, but also to preserve ovary function. OFS remains a main strategy for premenopausal women with HR-positive early breast cancer, though its exact role should be determined in further studies.
Aromatase ; Breast Neoplasms* ; Breast* ; Chemotherapy, Adjuvant ; Drug Therapy ; Estrogen Receptor Modulators ; Female ; Gonadotropin-Releasing Hormone ; Humans ; Medical Oncology ; Ovary ; Premenopause ; Receptors, Estrogen ; Tamoxifen

OBJECTIVETo investigate the effect of Shouwu Jiangqi Decoction (SJD) on polycystic ovary syndrome (PCOS) with insulin resistance (IR) in rats and to explore the underlining molecular mechanisms.

METHODSA total of 51 female Sprague-Dawley rats were randomly divided into 6 groups: control group (n=7), model group (n=8), SJD high-dose group (n=9), SJD medium-dose group (n=9), SJD low-dose group (n=9) and DMBG group (n=9). Radioimmunoassay was used to measure serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone concentrations and qRT-PCR and western blot were used to examine the expression levels of mRNA and protein respectively of insulin receptor substrate 1 (IRS-1) and phosphatidylinositide 3-kinases (PI3K) p85α in different groups.

RESULTSFSH level significantly decreased in the model group compared with the normal control (P<0.01), and high-dose SJD and DMBG can significantly increase FSH level (P<0.01). LH level showed a mild increase without statistic significance in the model group compared with the control and different dosages of SJD had no significance effect on LH level, while DMBG can significantly decrease LH level (P<0.01). Testosterone level significantly increased in the model group compared with the control group (P<0.01), and high-dose SJD and DMBG can significantly decrease testosterone level (P<0.01). The expression of IRS-1 as well as PI3Kp85α were significantly decreased in the model group compared with the normal control group at both mRNA (P<0.001) and protein (P<0.01) level, and both high-dose SJD and DMBG can enhance IRS-1 and PI3K expression (P<0.05).

CONCLUSIONSSJD has potent therapeutic effects on PCOS with IR in rats. The therapeutic effects of SJD on IR and ovulatory dysfunction are probably achieved through correcting the defective insulin signaling transduction.

Animals ; Blood Glucose ; metabolism ; Drugs, Chinese Herbal ; therapeutic use ; Fasting ; blood ; Female ; Follicle Stimulating Hormone ; blood ; Insulin ; blood ; Insulin Receptor Substrate Proteins ; metabolism ; Insulin Resistance ; Liver ; pathology ; Luteinizing Hormone ; blood ; Ovary ; pathology ; Phosphatidylinositol 3-Kinases ; metabolism ; Polycystic Ovary Syndrome ; blood ; drug therapy ; Rats, Sprague-Dawley ; Testosterone ; blood