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Diagnosis and Management of Growth Hormone Deficiency in Adults – Consultant360

Posted: July 16, 2022 at 2:00 am

AUTHORS:Alexandra Martirossian, MD1 Julie Silverstein, MD2

AFFILIATIONS:1Fellow, Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri

2Associate Professor of Medicine and Neurological Surgery, Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri

CITATION:Martirossian A, Silverstein J. Diagnosis and management of growth hormone deficiency in adults. Consultant.2022;62(6);e20-e27.doi:10.25270/con.2021.10.00004

Received July 25, 2021. Accepted August 27, 2021.Published online October 14, 2021.

DISCLOSURES:The authors report no relevant financial relationships.

CORRESPONDENCE:Julie Silverstein, MD, Washington University School of Medicine in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63110 (jsilverstein@wustl.edu)

Growth hormone deficiency (GHD) is a clinical syndrome caused by decreased production of or decreased tissue responsiveness to growth hormone. The most common cause of GHD in adults is pituitary tumors and their associated treatments of surgery or radiotherapy. Clinical manifestations of adult-onset GHD are nonspecific and include central obesity, loss of lean muscle mass, decreased bone density, insulin resistance, cardiovascular disease, hyperlipidemia, decreased exercise tolerance, and decreased quality of life. Diagnosis of GHD is confirmed by stimulatory testing or a low insulin-like growth factor 1 (IGF-1) level in the setting of multiple pituitary hormone deficiencies and organic pituitary disease. Treatment involves replacement with recombinant human growth hormone, and goals of therapy include clinical improvement, avoidance of adverse effects, and normalization of IGF-1 levels. Recombinant human growth hormone should only be prescribed for its approved clinical uses by an endocrinologist, and the risks and benefits of therapy should be weighed on a case-by-case basis.1,2

Physiology

Growth hormone (GH) is a polypeptide hormone secreted by somatotroph cells in the anterior pituitary that exerts several anabolic effects throughout the body. The GH receptor is expressed in multiple tissues including the liver, cartilage, muscle, fat, and kidneys.1 Activation of the GH receptor in the liver leads to hepatic production of insulin-like growth factor 1 (IGF-1), a peptide important for mediating many of GHs effects. In children, GH and IGF-1 are required for chondrocyte proliferation and linear growth. In adults, GH promotes several primarily anabolic effects including breakdown of fat, muscle growth, hepatic glucose production, and bone formation.1,3 Growth hormone secretion is regulated by a complex mixture of signals from the hypothalamus, gut, liver, and gonads, with production stimulated by growth hormone-releasing hormone (GHRH) from the hypothalamus and inhibited by somatostatin, which is primarily secreted in the brain and gastrointestinal tract. Factors that stimulate GH secretion include deep sleep, fasting, hypoglycemia, -adrenergic pathways, ghrelin, sex steroids, stress, and amino acids (eg, arginine, leucine).3 Factors that suppress GH secretion include obesity, glucocorticoids, glucose, hypothyroidism, IGF-1 (negative feedback), -adrenergic pathways, and free fatty acids. GH secretion is episodic and exhibits a diurnal rhythm with approximately two-thirds of the total daily GH secretion produced at night triggered by the onset of slow-wave sleep.3 GH levels reach a nadir during the day and may be undetectable, especially in obese or elderly persons. Over the course of a lifetime, GH secretion gradually rises during childhood, peaks during puberty, then gradually declines through adulthood. The phenomenon of age-related decline in GH levels is sometimes referred to as somatopause.4

Causes of Growth Hormone Deficiency

GHD can occur at any age and results from both congenital and acquired disorders (Table 1). Congenital causes include gene mutations and structural defects. Mutations in the genes encoding GH, GH receptor, GHRH receptor, and various transcription factors can cause GHD. Structural defects include empty sella syndrome, septo optic dysplasia, hydrocele, and pituitary hypoplasia.2 Acquired causes include intracranial tumors (eg, pituitary adenoma, craniopharyngioma, Rathke cleft cyst, glioma/astrocytoma, metastasis), head trauma, central nervous system infection, infarction (Sheehan syndrome), and infiltrative/granulomatous disease (eg, sarcoidosis, Langerhans cell histiocytosis, tuberculosis). GHD can also result from treatments for some of the aforementioned conditions, particularly cranial surgery or irradiation. In adults, the most common cause of GHD is a pituitary adenoma or treatment of the adenoma with pituitary surgery and/or radiotherapy, with the risk of deficiency proportional to the size of the tumor and extent of treatment.2

Manifestations of GHD in adults may include central obesity, loss of lean muscle mass, decreased bone mass, insulin resistance, cardiovascular disease, hyperlipidemia, and decreased quality of life.1 Data supporting the benefits of GH replacement are mixed, with much of the data showing benefit coming from retrospective and open-label observational studies. Some, but not all, studies show that GH replacement is associated with an increase in strength and exercise capacity2 and is associated with an increase in bone mineral density5,6 and decreased fracture risk.7 In terms of cardiovascular disease, a metanalysis of randomized, blinded, placebo-controlled trials suggests that GH replacement increases lean body mass and decreases fat mass, has a beneficial effect on low-density lipoprotein cholesterol, and lowers diastolic blood pressure8, but there is no evidence that these changes are associated with measurable changes in cardiovascular function.9

Benefits of Growth Hormone Deficiency

The effect of GH replacement on glucose metabolism is complex. GH antagonizes the action of insulin, and evidence suggests that GH replacement may lead to a transient increase in fasting glucose10 but not necessarily an increased incidence of diabetes.11 Long-term observational studies of patients with adult GHD also suggest that GH replacement is associated with an improvement in quality of life when assessing parameters such as memory and concentration, fatigue, tenseness, socializing, and self-confidence.12,13

Diagnosing Growth Hormone Deficiency

Making the diagnosis of GHD is generally easier in children because the outcome of short stature is readily apparent. The task is more difficult in those with adult-onset deficiency because the symptoms are generally nonspecific, so a higher index of suspicion is required.

Because of the high financial cost of recombinant human growth hormone (rhGH) and possibility of adverse effects, it is crucial that the correct diagnosis is made and that treatment is only pursued in those adults who are truly GH deficient. This shrewdness is important for prevention of inappropriate treatment that is sometimes seen in nonmedical conditions such as aging and sports. In deciding who to screen, a clinical history guides the extent of required testing (Figure).

In adults with a history of organic hypothalamic-pituitary disease (eg, pituitary mass with previous surgery and cranial irradiation) with at least 3 hormone deficiencies (eg, hypothyroidism, adrenal insufficiency, and hypogonadism) and a low serum IGF-1 level (< 2.0 standard deviation score, also reported as a Z-score), no further testing is required, and treatment can be initiated.14 This also applies to adults who have congenital structural defects or genetic mutations affecting the hypothalamic-pituitary axes who have at least 3 other hormone deficiencies and low serum IGF-1 level. In adults who have a history of organic hypothalamic-pituitary disease with 2 or fewer hormone deficiencies, high clinical suspicion, and a low IGF-1 level (< 0 standard deviation score), provocative testing for GHD is indicated.14

In the absence of any of these risk factors, testing is not advised. It should be noted that 30% to 40% of patients with adult-onset GHD may have normal IGF-1 levels, so if clinical suspicion remains high, diagnostic testing should be pursued.15 In adults with idiopathic GHD in childhood, retesting should be performed because a significant proportion of this population may have normal GH secretion as adults.16-19

Figure. Algorithm for Stimulation Testing and Treatment in Adults With Suspected Growth Hormone Deficiency14

Measurement of random GH levels for the purpose of diagnosing GHD is not reliable for multiple reasons. First, GH has a short circulating half-life of only 10 to 20 minutes, and the pulsatility of GH secretion makes interpretation of single measurements difficult.20 Second, GH secretion is suppressed in the postprandial state, so timing of food consumption is important to know. Other factors associated with decreased IGF-1 levels that should be taken into consideration when interpreting laboratory test results include advanced age, obesity, poorly controlled diabetes, liver disease, renal failure, oral estrogen use, hypothyroidism, and critical illness.21 Additionally, assays for GH and IGF-1 have not been rigorously standardized, and normal baseline values for adults are often inadequate. To circumvent these diagnostic issues, GH stimulation tests are used. There are several GH provocative tests available in clinical practice (Table 2), each with its own advantages and disadvantages.

The insulin tolerance test (ITT), although not commonly used in the United States, is considered the gold standard for diagnosis of GHD.4,14,22 Insulin-induced hypoglycemia stimulates the release of GH. The ITT is performed by having the patient fast for at least 8 hours and then intravenous insulin is administered at a dose of 0.05 to 0.15 U/kg. Blood is drawn fasting and then 20, 30, 40, and 60 minutes after adequate hypoglycemia is achieved (blood glucose, < 40 mg/dL).22,23 The diagnostic cutoff for GHD is a GH level 5 g/L or lower after hypoglycemia is achieved. The positive predictive value is 93%, sensitivity is 96%, and specificity is 92%.22 Several drawbacks of the ITTincluding the requirement for close medical supervision by a physician throughout the test, the possibility of inducing severe life-threatening hypoglycemia, and the risk of causing seizures and altered consciousness in certain susceptible populationslimit its use. The ITT is contraindicated in individuals aged older than 65 years, those who are pregnant, and those who have a history of or are at risk for seizures and cardiovascular disease. Moreover, normoglycemic or hyperglycemic patients with obesity and insulin resistance may require higher doses of insulin (0.15-0.2 U/kg) to achieve target hypoglycemia, thus increasing their risk for delayed hypoglycemia.

Finding an alternative to the ITT for the diagnosis of GHD has been challenging. The GHRH-arginine stimulation test showed favor for some time because of its convenience, reproducibility, and discriminatory power. However, in 2008, the recombinant GHRH (ie, injectable sermorelin) was removed from the market, so the test could no longer be performed in the United States.14,22 Since then, the glucagon stimulation test (GST) has become a preferred alternative diagnostic test for GHD in the United States. The exact mechanism for how glucagon stimulates GH secretion is poorly understood, but it has been shown to be a more-potent stimulator of GH secretion than other agents, including arginine and clonidine.24,25 Glucagon is more effective at stimulating GH secretion when administered intramuscularly compared with intravenously.26 The GST is performed by first having the patient fast for 8 to 10 hours, and then intramuscular glucagon is administered (1 mg if weight is 90 kg, 1.5 mg if weight is > 90 kg). Serum GH and blood glucose levels are measured at 0, 30, 60, 90, 120, 150, 180, 210, and 240 minutes after glucagon is administered. A GH cutoff of 3 g/L has been shown to have sensitivity and specificity of up to 100% in lean subjects (body mass index, 25 kg/m2).22 However, because obesity blunts the GH secretion response to glucagon, a lower cutoff of 1 g/L is recommended in individuals who are overweight or obese (body mass index, > 25 kg/m2).22 Advantages of the GST include its availability, reproducibility, safety, lack of influence by gender and hypothalamic cause of GHD, and relatively few contraindications. Disadvantages include its long duration, the need for intramuscular administration and multiple blood draws, and gastrointestinal adverse effects. The test is contraindicated in malnourished individuals or individuals who have not eaten for more than 48 hours, as well as those with severe fasting hyperglycemia (> 180 mg/dL).22,23 Because late hypoglycemia may occur, individuals should be advised to eat small and frequent meals after completion of the test.

In 2017, the US Food and Drug Administration (FDA) granted approval for the use of macimorelin for diagnosing adult GHD.27 Macimorelin acetate is an oral ghrelin receptor agonist with GH secretagogue activity that is readily absorbed and effectively stimulates endogenous GH secretion in healthy volunteers with good tolerability.28 To validate the efficacy and safety of macimorelin in the diagnosis of adult GHD, Garcia and colleagues performed an open-label, randomized, multicenter, 2-way crossover study of the macimorelin test vs the ITT.29 Participants with high (n = 38), intermediate (n = 37), and low (n = 39) likelihood for adult GHD and healthy, matched controls (n = 25) were included in the efficacy analysis. The macimorelin oral solution was prepared at a dose of 0.5 mg/kg of body weight. Blood samples for GH serum levels were collected before and at 30, 45, 60, and 90 minutes after administration of macimorelin. Using a GH cutoff of 2.8 ng/mL for the macimorelin test and 5.1 ng/mL for the ITT, the sensitivity was 87% and specificity was 96%. In post-hoc analyses, increasing the GH cutoff for the macimorelin test to 5.1 ng/mL while maintaining the GH cutoff of 5.1 ng/mL for the ITT resulted in a sensitivity of 92% and specificity of 96%. A greater peak GH level was seen in all groups with the macimorelin test compared with the ITT. Reproducibility for macimorelin was high at 97%. The macimorelin test was well tolerated with no serious or frequent adverse effects reported. The most common adverse effect was mild and transient dysgeusia. Garcia and colleagues later performed post-hoc analyses to determine whether macimorelin performance was affected by age, body mass index, or sex and evaluated its performance vs ITT over a range of GH cutoffs.30 They found that macimorelin performance was not meaningfully affected by age, body mass index, or sex. Caution should be used in generalizing these results in pediatric, elderly, and severely obese patients, since the study population age range was 18 to 66, and the highest recorded baseline body mass index was 36.6 kg/m2, with most participants having a body mass index of less than 30 kg/m2. Of the 4 GH cutoffs evaluated (2.8 ng/mL, 4.0 ng/mL, 5.1 ng/mL, and 6.5 ng/mL), the cutoff of 5.1 ng/mL provided maximal specificity (96%) and high sensitivity (92%) and was in good overall agreement with the ITT at the same cutoff (87%). At present, the approved FDA cutoff is the lower value of 2.8 ng/mL.29 Compared with the ITT and GST, the macimorelin stimulation test has the advantages of being safer, well tolerated, easier to perform, and is less influenced by body weight, so its use in clinical practice may increase in coming years. A major factor currently limiting its widespread use is high financial cost.14

Treatment of Growth Hormone Deficiency

Once the diagnosis of GHD has been made, treatment is initiated with rhGH, which contains the identical sequence of amino acids found in HGH. For many years, the only rhGH product on the US market was somatropin, a once-daily injection. In September 2020, the FDA approved once-weekly somapacitan for the treatment of adult GHD, but it is not yet available on the market.31,32 It is hoped that the decreased frequency of injections should lower the burden of treatment and improve treatment adherence. Multiple brands of somatropin are available, and there is no evidence that one commercial product is different or more advantageous than another, apart from differences in pen devices, electronic autoinjector devices that are user-friendly, dose per milligram adjustments, and whether the product requires refrigeration.14

In adults, the typical dose of somatropin ranges from 0.1 to 0.4 mg/d and is influenced by age, sex, comorbidities, and concomitant medications. Per the 2019 guidelines published by the American Association of Clinical Endocrinologists (AACE), the recommended starting dose for patients aged younger than 30 years is 0.4 to 0.5 mg/d, aged between 30 to 60 years is 0.2 to 0.3 mg/d, and aged older than 60 years is 0.1 to 0.2 mg/d. In patients transitioning from pediatric to adult care, rhGH should be continued at 50% of the dose used in childhood and then gradually adjusted. In patients with concurrent type 2 diabetes, previous gestational diabetes, and obesity, lower doses of 0.1 to 0.2 mg/d are recommended. Women tend to require higher doses than men to achieve the same IGF-1 level, especially if they are taking oral estrogen.33,34 Approximately 85% of circulating IGF-I is liver derived, and oral estrogen, which undergoes first pass metabolism, suppresses hepatic production of IGF-1. rhGH dose reduction is often necessary when oral estrogen is stopped or switched to transdermal. Most adverse effects of treatment are dose related. The most common adverse effects are related to insulin resistance and fluid retention and include hyperglycemia, paresthesias, joint stiffness, peripheral edema, arthralgias, myalgias, and carpal tunnel syndrome.2 Contraindications to treatment include active malignancy and active proliferative or severe nonproliferative diabetic retinopathy.

After GH replacement therapy is initiated, it is recommended that patients follow-up in 1- or 2-month intervals at first, which can later be spaced out to 6- or 12-month intervals once a stable dose has been reached.14 Determination of the appropriate dose is influenced by multiple factors, including clinical improvement in symptoms, avoidance of adverse effects, and IGF-1 level. Assessment of fasting glucose, hemoglobin A1c, fasting lipids, body mass index, waist circumference, waist-to-hip ratio, and quality of life should be performed at least once per year. Assessment of other pituitary hormone deficiencies and structural pituitary lesions with laboratory and imaging studies, respectively, should be performed as clinically indicated. If the initial bone density scan is abnormal, repeat evaluations at 2- to 3-year intervals are recommended. IGF-1 levels are commonly used to guide the adequacy of rhGH dosing, and the general recommendation is to target a level within age-adjusted reference ranges (standard deviation score, 2 and +2). However, studies have shown varying benefits and drawbacks to targeting IGF-1 levels in the upper or lower half of this range. Targeting IGF-1 levels in the upper range of normal (standard deviation score, 1-2) has shown benefits in body fat composition, waist circumference, and microcirculatory function but at the expense of increased insulin resistance and myalgias.35,36 Targeting IGF-1 levels in the lower range of normal (standard deviation score, 2 to 1) is more often associated with fatigue. Women may have a narrower therapeutic dose window than men. In a study by van Bunderen and colleagues, a high-normal IGF-1 target level in female study participants was associated with impaired prefrontal cognitive functioning, whereas a low-normal target IGF-1 level was associated with decreased vigor.37

The question of how long to continue GH replacement therapy is frequently debated. If clinical benefits have resulted from treatment (eg, improved quality of life, body composition, cardiovascular health, bone density), rhGH can be continued indefinitely presuming there are no contraindications. If there are neither subjective nor objective benefits after at least 12 to 18 months of treatment, the option of discontinuing GH replacement should be discussed with the patient.2,14 Since GH promotes cellular proliferation and tissue growth, there has been a longstanding theoretical concern that rhGH leads to increased risk of malignancy. Although studies show no increased risk of malignancy in hypopituitary patients on long-term growth hormone treatment, an abundance of caution should be exercised when deciding whether to start rhGH in patients with GHD and a history of or genetic predisposition to malignancy.38 It has been suggested that in adult patients with a history of cancer, low-dose rhGH should only be initiated 5 years after cancer remission is achieved.14,39 The patients oncologist should be in agreement and closely involved in follow-up care while the patient is taking therapy. In all patients, regardless of cancer risk, cancer screening guidelines should be followed.

A topic that has gained much attention in our culture is the use of GH for antiaging, with some citing it as a fountain of youth.40 Despite the popularity of this idea, no studies have assessed long-term (> 6 months) efficacy or safety of rhGH administration for this purpose in humans.14 Paradoxically, studies performed in mice have shown that mice with isolated GHD caused by GHRH or GHRH receptor mutations, combined deficiency of GH, prolactin, and thyroid-stimulating hormone, or global deletion of GH receptors live longer than their normal siblings and exhibit multiple features of delayed and/or slower aging.41-43 Liu and colleagues performed a meta-analysis of 31 studies describing the use of GH in healthy elderly adults and found that GH use was associated with small changes in body composition but increased rates of adverse events.44 In the United States, off-label distribution or marketing of rhGH to treat aging or aging-related conditions and for the enhancement of athletic performance is illegal. Given the clinical concerns and legal issues involved, it is strongly recommended that rhGH only be prescribed for the well-defined approved uses of the medication, which are GHD and HIV-associated lipodystrophy.14,45,46

Conclusions

Growth hormone replacement therapy in adults with confirmed GHD has been shown to be associated with improvement in multiple aspects of health, including body composition, muscle mass, cardiovascular health, bone density, and quality of life. The clinical manifestations of GHD in adults are often nonspecific, so diligence to confirm an accurate diagnosis is essential for avoiding the costs and ethical dilemmas of inappropriate treatment. There are multiple GH stimulatory tests available, each with its own benefits and caveats. Once the diagnosis of adult GHD is established, rhGH should be initiated at low doses and uptitrated based on IGF-1 levels and symptoms, while avoiding adverse effects. Research into longer-acting rhGH formulations and enhanced diagnostic testing is ongoing and will be essential for guiding the management of adult GHD.

References

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14. Yuen KCJ, Biller BMK, Radovick S, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of growth hormone deficiency in adults and patients transitioning from pediatric to adult care. Endocr Pract. 2019;25(11):1191-1232. https://doi.org/10.4158/gl-2019-0405

15. Hilding A, Hall K, Wivall-Helleryd IL, Sf M, Melin AL, Thorn M. Serum levels of insulin-like growth factor I in 152 patients with growth hormone deficiency, aged 19-82 years, in relation to those in healthy subjects. J Clin Endocrinol Metab. 1999;84(6):2013-2019. https://doi.org/10.1210/jcem.84.6.5793

16. Maghnie M, Strigazzi C, Tinelli C, et al. Growth hormone (GH) deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults. J Clin Endocrinol Metab. 1999;84(4):1324-1328. https://doi.org/10.1210/jcem.84.4.5614

17. Wacharasindhu S, Cotterill AM, Camacho-Hbner C, Besser GM, Savage MO. Normal growth hormone secretion in growth hormone insufficient children retested after completion of linear growth. Clin Endocrinol (Oxf). 1996;45(5):553-556. https://doi.org/10.1046/j.1365-2265.1996.00850.x

18. Longobardi S, Merola B, Pivonello R, et al. Reevaluation of growth hormone (GH) secretion in 69 adults diagnosed as GH-deficient patients during childhood. J Clin Endocrinol Metab. 1996;81(3):1244-1247. https://doi.org/10.1210/jcem.81.3.8772606

19. Nicolson A, Toogood AA, Rahim A, Shalet SM. The prevalence of severe growth hormone deficiency in adults who received growth hormone replacement in childhood. Clin Endocrinol (Oxf). 1996;44(3):311-316. https://doi.org/10.1046/j.1365-2265.1996.671492.x

20. Iranmanesh A, Lizarralde G, Veldhuis JD. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. J Clin Endocrinol Metab. 1991;73(5):1081-1088. https://doi.org/10.1210/jcem-73-5-1081

21. Kwan AY, Hartman ML. IGF-I measurements in the diagnosis of adult growth hormone deficiency. Pituitary. 2007;10(2):151-157. https://doi.org/10.1007/s11102-007-0028-8

22. Yuen KC, Tritos NA, Samson SL, Hoffman AR, Katznelson L. American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: update on growth hormone stimulation testing and proposed revised cut-point for the glucagon stimulation test in the diagnosis of adult growth hormone deficiency. Endocr Pract. 2016;22(10):1235-1244. https://doi.org/10.4158/ep161407.dscr

23. Yuen KCJ. Growth hormone stimulation tests in assessing adult growth hormone deficiency. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. MDText.com, Inc.; November 1, 2019. http://www.ncbi.nlm.nih.gov/books/nbk395585/

24. Rahim A, Toogood AA, Shalet SM. The assessment of growth hormone status in normal young adult males using a variety of provocative agents. Clin Endocrinol (Oxf). 1996;45(5):557-562. https://doi.org/10.1046/j.1365-2265.1996.00855.x

25. Aimaretti G, Baffoni C, DiVito L, et al. Comparisons among old and new provocative tests of GH secretion in 178 normal adults. Eur J Endocrinol. 2000;142(4):347-352. https://doi.org/10.1530/eje.0.1420347

26. Ghigo E, Bartolotta E, Imperiale E, et al. Glucagon stimulates GH secretion after intramuscular but not intravenous administration. Evidence against the assumption that glucagon per se has a GH-releasing activity. J Endocrinol Invest. 1994;17(11):849-854. https://doi.org/10.1007/bf03347790

27. Macrilen (macimorelin) for Oral Solution. US Food & Drug Administration. Published January 31, 2018. Accessed March 14, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/205598Orig1s000TOC.cfm

28. Piccoli F, Degen L, MacLean C, et al. Pharmacokinetics and pharmacodynamic effects of an oral ghrelin agonist in healthy subjects. J Clin Endocrinol Metab. 2007;92(5):1814-1820. https://doi.org/10.1210/jc.2006-2160

29. Garcia JM, Biller BMK, Korbonits M, et al. Macimorelin as a diagnostic test for adult GH deficiency. J Clin Endocrinol Metab. 2018;103(8):3083-3093. https://doi.org/10.1210/jc.2018-00665

30. Garcia JM, Biller BMK, Korbonits M, et al. Sensitivity and specificity of the macimorelin test for diagnosis of AGHD. Endocr Connect. 2021;10(1):76-83. https://doi.org/10.1530/ec-20-0491

31. FDA approves weekly therapy for adult growth hormone deficiency. News Release. US Food & Drug Administration. Published September 1, 2020. Accessed March 27, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-weekly-therapy-adult-growth-hormone-deficiency

32. Johannsson G, Gordon MB, Hjby Rasmussen M, et al. Once-weekly somapacitan is effective and well tolerated in adults with GH deficiency: a randomized phase 3 trial. J Clin Endocrinol Metab. 2020;105(4):e1358-e1376. https://doi.org/10.1210/clinem/dgaa049

33. Burman P, Johansson AG, Siegbahn A, Vessby B, Karlsson FA. Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. J Clin Endocrinol Metab. 1997;82(2):550-555. https://doi.org/10.1210/jcem.82.2.3776

34. Cook DM, Ludlam WH, Cook MB. Route of estrogen administration helps to determine growth hormone (GH) replacement dose in GH-deficient adults. J Clin Endocrinol Metab. 1999;84(11):3956-3960. https://doi.org/10.1210/jcem.84.11.6113

35. van Bunderen CC, Lips P, Kramer MH, Drent ML. Comparison of low-normal and high-normal IGF-1 target levels during growth hormone replacement therapy: a randomized clinical trial in adult growth hormone deficiency. Eur J Intern Med. 2016;31:88-93. https://doi.org/10.1016/j.ejim.2016.03.026

36. van Bunderen CC, Meijer RI, Lips P, Kramer MH, Sern EH, Drent ML. Titrating growth hormone dose to high-normal IGF-1 levels has beneficial effects on body fat distribution and microcirculatory function despite causing insulin resistance. Front Endocrinol (Lausanne). 2021;11:619173. https://doi.org/10.3389/fendo.2020.619173

37. van Bunderen CC, Deijen JB, Drent ML. Effect of low-normal and high-normal IGF-1 levels on memory and wellbeing during growth hormone replacement therapy: a randomized clinical trial in adult growth hormone deficiency. Health Qual Life Outcomes. 2018;16(1):135. https://doi.org/10.1186/s12955-018-0963-2

38. Child CJ, Conroy D, Zimmermann AG, Woodmansee WW, Erfurth EM, Robison LL. Incidence of primary cancers and intracranial tumour recurrences in GH-treated and untreated adult hypopituitary patients: analyses from the Hypopituitary Control and Complications Study. Eur J Endocrinol. 2015;172(6):779-790. https://doi.org/10.1530/eje-14-1123

39. Yuen KC, Heaney AP, Popovic V. Considering GH replacement for GH-deficient adults with a previous history of cancer: a conundrum for the clinician. Endocrine. 2016;52(2):194-205. https://doi.org/10.1007/s12020-015-0840-2

40. DiGiorgio L, Sadeghi-Nejad H. Growth hormone and the fountain of youth. J Sex Med. 2018;15(9):1208-1211. https://doi.org/10.1016/j.jsxm.2018.04.647

41. Bartke A, Darcy J. GH and ageing: pitfalls and new insights. Best Pract Res Clin Endocrinol Metab. 2017;31(1):113-125. https://doi.org/10.1016/j.beem.2017.02.005

42. Aguiar-Oliveira MH, Bartke A. Growth hormone deficiency: health and longevity. Endocr Rev. 2019;40(2):575-601. https://doi.org/10.1210/er.2018-00216

43. Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A. 2001;98(12):6736-6741. https://doi.org/10.1073/pnas.111158898

44. Liu H, Bravata DM, Olkin I, et al. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med. 2007;146(2):104-115. https://doi.org/10.7326/0003-4819-146-2-200701160-00005

45. Clemmons DR, Molitch M, Hoffman AR, et al. Growth hormone should be used only for approved indications. J Clin Endocrinol Metab. 2014;99(2):409-411. https://doi.org/10.1210/jc.2013-4187

46. Burgess E, Wanke C. Use of recombinant human growth hormone in HIV-associated lipodystrophy. Curr Opin Infect Dis. 2005;18(1):17-24. https://doi.org/10.1097/00001432-200502000-00004

Read the original:
Diagnosis and Management of Growth Hormone Deficiency in Adults - Consultant360

Promoting adherence to r-hGH therapy | PPA – Dove Medical Press

Posted: July 16, 2022 at 2:00 am

Martin O Savage,1 Luis Fernandez-Luque,2 Selina Graham,3 Paula van Dommelen,4 Matheus Araujo,5 Antonio de Arriba,6 Ekaterina Koledova7

1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, London, UK; 2Adhera Health Inc., Palo Alto, CA, USA; 3Kings College London, London, UK; 4The Netherlands Organization for Applied Scientific Research TNO, Leiden, the Netherlands; 5Neurological Institute; Cleveland Clinic, Cleveland, OH, USA; 6Paediatric Endocrinology, Hospital Universitario Miguel Servet, Zaragoza, Spain; 7Global Medical Affairs Cardiometabolic & Endocrinology, Merck Healthcare KGaA, Darmstadt, Germany

Correspondence: Martin O Savage, Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Charterhouse Square, London, EC1M 6BQ, UK, Tel +44 7803084491, Email [emailprotected]

Abstract: Pediatric growth hormone (GH) deficiency is a licensed indication for replacement therapy with recombinant human growth hormone (r-hGH). Treatment, consisting of daily subcutaneous injections, extends from the time of diagnosis until cessation of linear growth at completion of puberty. Suboptimal adherence to r-hGH therapy is common and has been well documented to substantially impair the growth response and achievement of the optimal goal which is attainment of adult height within the genetic target range. The causes of poor adherence are complex and include disease-, patient-, doctor-, and treatment-related factors. Interventions for suboptimal adherence are important for a long-term successful outcome and can include both face-to-face and digital strategies. Face-to-face interventions include behavioral change approaches such as motivational interviewing and non-judgmental assessment. Medical and nursing staff require training in these techniques. Digital solutions are rapidly advancing as evidenced by the electronic digital auto-injector device, easypod (Merck Healthcare KGaA, Darmstadt, Germany), which uses the web-based easypod connect platform allowing adherence data to be transmitted electronically to healthcare professionals (HCPs), who can then access GH treatment history, enhancing clinical decisions. Over the past 10 years, the multi-national Easypod Connect Observational Study has reported high levels of adherence (> 85%) from up to 40 countries. The easypod connect system can be supported by a smartphone app, growlink, which facilitates the interactions between the patients, their care team, and patient support services. HCPs are empowered by new digital techniques, however, the humandigital partnership remains essential for optimal growth management. The pediatric patient on r-hGH therapy will benefit from these innovations to enhance adherence and optimize long-term response.

Adherence to a therapeutic regimen is an essential component of the success of any prescribed therapy. In the case of treatment of pediatric growth disorders, prescribed therapy in the form of recombinant human growth hormone (r-hGH) will generally be started in early childhood when the child presents with short stature and continued for many years. The aim is to normalize height during childhood and adolescence and achieve an adult height consistent with the genetic target of the family.1 Such a therapeutic regimen, consisting of daily subcutaneous injections lasting for many years, places a considerable psychological and physical burden on the patient to adhere. There is also a pressure on healthcare professionals (HCPs) responsible for this care to induce a beneficial long-term result.2

Two important considerations linked to good adherence to r-hGH are necessary for optimal outcomes. These are, first, the extent to which the patients behavior matches agreed recommendations from their HCP and, second, persistence with the therapy, ie lack of discontinuation.3 Adherence can be defined as the extent to which the patient follows a prescribed therapeutic regimen and, in the case of r-hGH, the extent to which daily r-hGH injections are taken. The success of r-hGH therapy, as in other chronic conditions, is thought to be dependent on the patients ability to maximally adhere to their treatment regimen.2,3

In this review, we will discuss the challenges, both to the patient and HCP, of maintaining a high level of adherence to r-hGH, and the factors which have been shown to influence adherence both negatively and positively. We will summarize feedback data from both HCPs and patients, and discuss knowledge from other more advanced therapeutic areas regarding the importance of data generation and analysis to understand how to positively support adherence. Our aim is to look forward to future developments in digital health which will positively impact on adherence. We will discuss the contribution of behavioral support and its digitalization as a means of supporting the family and patient, and conclude by debating the importance of design of adherence support, with continuous evaluation cycles of new digital tools, in order to achieve maximal personalized impact on the adherence paradigm and the patients journey.

Since the development and widespread clinical use of r-hGH in 1985, a range of growth disorders have been approved for this treatment by regulatory organizations such as the US Food and Drug Administration and European Medicines Agency.4 Initially, GH deficiency (GHD) was approved, followed by non-GH-deficient disorders such as Turner syndrome, short stature related to birth size small for gestational age (SGA), and idiopathic short stature.5 Treatment of these disorders until adult height is reached is, by definition, demanding and the issue of good adherence to the prescribed therapy is highly relevant to the final outcome.6

Thus, begins a multi-year journey involving daily injections and regular consultation visits (typically every 6 months) to assess growth and metabolic parameters. Along this journey and depending on the healthcare setting, the child and his/her parents receive various levels of information, support, and encouragement to comply with the therapy regimen. HCPs may also be involved in dealing with clinical, emotional, and behavioral issues that may arise during teenage years. Adolescents with GHD may require transitional care and continued r-hGH therapy through into adulthood to optimize body composition maturation and metabolic factors that could adversely affect their cardiovascular health.7,8

Factors adversely affecting adherence which are encountered by HCPs include managing clinical, emotional, and behavioral issues arising during teenage years.9 Other factors shown to be strongly associated with non-adherence and lack of persistence include poor understanding of both the condition and consequences of missed r-hGH doses, injection discomfort, dissatisfaction with growth outcomes compared with pediatric endocrinologist predictions, and inadequate or problematic contact with HCPs.10

Digital health technologies have become an essential part of daily life and, consequently, they have high potential to support patients and caregivers in their health management. As early as 1996, research showed the positive impact of digital tools in diabetes patient education for children.11 However, the wider adoption and implementation of such technologies is still a major challenge.12 The scientific community has been looking into many factors that address adoption and acceptance of technologies and these often highlight human factors such as usability, perceived usefulness, and literacy levels.13,14 These factors related to the adoption of technology have some similarities to drivers for medication adherence,1517 including education or how the medication is being introduced.

Addressing the patients and caregivers perspectives is crucial, especially in areas where digital health interventions are supporting medication adherence or other long-term self-management behaviors. In the case of digital interventions in pediatrics, a key aspect to consider is the interplay between caregivers and patients especially during the transition to adult care18 or patient-initiated medication. For example, a key moment to intervene is when injections are transitioning from being delivered by the caregivers to the children themselves.

In recent years, a lot of effort has been put into the use of new methodologies to capture end-users feedback when using digital interventions, including participatory research and design research.19 Such methodologies facilitate the capture of feedback and the perspective of patients and caregivers for adjusting behavioral interventions.20 This feedback can then be used to adjust digital interventions to minimize adoption challenges. For example, the project Sisom (from the Norwegian phrase Si det Som det er, meaning Tell it how it is) focused on capturing the feedback of children with chronic conditions using a child-friendly patient-reported outcome mobile solution designed to enhance nursepatient relationships.21 Another example is the mobile solution Pain Squad for children with oncologic pain, for example, where patients were heavily involved in the design to maximize adherence to the use of the mobile-based pain diary.22 A more recent example, explained below, is the CARING study which focuses on the feasibility of supporting the emotional wellbeing of caregivers in a mobile-based digital intervention.23

Several factors are important when capturing feedback from patients and caregivers for the development of digital health interventions. Studies have shown that socio-cultural factors such as gender, ethnicity, and education level are relevant in the adoption of such digital health technologies.2426 Also, caregivers and patients perspectives concerning digital health interventions should be included in the analysis of healthcare delivery since, in most cases, the roll-out and implementation of such solutions will impact the provision of healthcare. To address this service delivery angle, methods aligned with service design are often applied.14 Finally, emerging research highlights the relevance of addressing digital health literacy as an enabler for adoption. Consequently, it represents a major aspect to consider when studying the patients and caregivers perspectives. For example, high levels of digital health literacy reduce risks regarding the adoption and safe usage of digital health tools by both caregivers and patients.27

There are several ways of administering r-hGH to pediatric patients, including syringes, pens, and auto-injector devices. One such device, the easypod autoinjector, transmits data to a web-based platform that allows HCPs to monitor adherence and access longitudinal patient data. To test the impact of this digital ecosystem on adherence, the Easypod Connect Observational Study (ECOS) was performed across multiple countries.28 The ECOS demonstrated how a digital health ecosystem, that records dose, date, and time of r-hGH administration, can help to maintain high adherence (85%; mg injected/mg prescribed) over the course of several years in different countries.28 Real-world data extracted from the easypod connect ecosystem support these findings. In an analysis performed from 2007 to the end of 2020, adherence data were available for 20,264 patients from 38 countries.29,30 Levels of high adherence increased over time in European (76% in 2010; 8284% in 20152019; 86% in 2020), North American (Canadian) (65% in 2010; 68% in 2015; 88% in 20192020), and Asian (5862% in 20142015; 6873% in 20162020) patients.29,30 No consistent change in adherence was found among Latin-American and Caribbean patients.29,30 Importantly, the observed adherence levels also had a statistically significant effect on change in Height Standard Deviation Scores (HSDS) from treatment start. Mean HSDS were 0.4, 0.7, 1.0, and 1.1 after 12, 24, 36, and 48 months treatment, respectively, in patients with high (85%) monthly adherence, 0.3, 0.6, 0.8, and 0.9 in patients with intermediate (>5684%) monthly adherence and 0.2, 0.5, 0.6, and 0.7 in patients with low (56%) monthly adherence.29,30

Expansion of digital health ecosystems, like easypod connect, through addition of new digital tools that have been co-created with HCPs and patients, offers an exciting opportunity to further improve both adherence and clinical outcomes for patients with growth disorders. When developing such digital tools, we propose following an iterative cycle that leverages the use of patient-generated data (Figure 1). The approach implies that defined hypotheses are validated based on patient-generated data prior to the design of prototypes, which are then tested in a clinical setting as the basis for future hypotheses. This continuous feedback loop can help pinpoint areas for improvement based on pre-defined patient populations. First, a team of interdisciplinary HCPs defines a hypothesis to improve management towards an optimal outcome based on their clinical experience. For example, they propose a mathematical model that predicts future therapy response based on experience and demographic information. Once the hypothesis has been thoroughly defined, data scientists use information from connected devices and other data sources, such as electronic health records, to develop, analyze, and validate data-driven models in an experimental setting. If successful, an experimental model (prototype) is designed and tested in collaboration with the HCP team, taking end-user feedback into consideration. An enhanced digital ecosystem is then established as the basis for real-world evaluation of (determinants) of use and outcome, for example, in prospective clinical trials. This enhanced ecosystem not only has the potential to improve disease management, but also serves as the basis for hypothesis generation within the next iterative loop. Over time, with increased patient-generated datasets, improved synergy between experienced teams, and new assumptions and hypotheses, this agile and incremental approach to the development of digital ecosystems will reflect the evolution of healthcare provision.

Figure 1 Continuous feedback loop based on patient-generated data. The data provided by patients, the HCP team and data scientists contribute to the development of an enhanced ecosystem.

To complement digital solutions, the use of psychology-based approaches within the healthcare environment can be beneficial to support HCPs in learning how to help patients to make healthy choices and decisions in their lives. HCPs are uniquely positioned within clinical settings to monitor, support, and promote adherence behaviors due to their existing supporting relationships with patients and their families.31 Importantly, HCPs are trusted by their patients and are often the people patients will turn to when they are thinking about making a health-related change. Addressing adherence-related issues within routine clinical practice can be a struggle, as patients and/or their families generally find it difficult to talk openly about adherence and are often reluctant or apprehensive to disclose treatment non-adherence.32 Thus, it is important for medical and nursing HCPs to be supported in core training to develop and reinforce key consultation behaviors and skills, ie motivational interviewing (MI).33

MI is a skill which can benefit both medical and nursing HCPs. Examples of the benefits of MI can be taken from experience in making healthy life choices. When considering these choices, reaction to the individual can be unhelpful, such as not listening or negatively encouraging regressive behavior. By contrast, a helpful response to the same life choices would consist of positive reactions such as genuine empathetic listening and exploration of the individuals feelings without judgement. This behavior typifies the spirit of MI, the key principles of which are partnership, acceptance, compassion, and evocation (PACE). Collaboration is important because partnership on an equal level with the patient is a key aim. Acceptance leads to better understanding of the decisions and choices that patients and families are making without judgement. These choices are accepted and the HCP responds with guidance. Compassion is a further component that is combined with Evocation, which means drawing out a patients inner motivation and commitment, and building on this to effect change.2,33

Core skills in MI can be discussed under the acronym OARS, which stands for Open questions, Affirmations, Reflective listening, and Summarising.2,33 The conversation can be structured by following these headings. Open questions such as what, how, and why will open conversations and evoke dialogue. Other examples would be what are your hopes for your consultation today? and I am curious to learn how you have been getting on with your injections? These questions can be prefaced by saying help me understand and the conversation can develop by inviting the patient or family to talk about what is on their mind and what their needs and their priorities are. Affirmations are about helping patients to recognize their own strengths and positive beliefs that are going to help them to adhere to r-hGH therapy. Examples could be to say to a patient, I can see it took courage for you to try this out today or to a parent, your creative ideas around this are very helpful. Reflective listening consists of not only listening and reflecting back what is said, it also helps in verbalizing the thinking and feelings that lie underneath, showing a depth of empathy that leads to further conversations. The last skill here is summarizing, which serves the useful purpose of wrapping up conversations and can be started by saying let me see if I have got this right, you are feeling this on one hand and perhaps feeling this on the other?.

Pediatric endocrinology nurse specialists can play a key role in addressing and managing the needs of patients prescribed r-hGH treatment and their families within their medical consultations. In view of this, psychologically-based patient support programs (PSPs) have been designed to help support patients and families to better manage their condition and treatment, with the purpose to optimize treatment adherence and improve clinical outcomes. These programs have demonstrated improved outcomes in a wide variety of diseases, through multidisciplinary HCP training and coaching; therefore, it is crucial for HCPs to begin to implement these new approaches within clinical practice in order to make a positive impact.34,35

One such PSP is TuiTek, a digital, multicomponent, personalized program designed to support the needs of patients, caregivers, and HCPs throughout the treatment care pathway. The intervention comprises two key service components: 1) a PSP training session, which aims to provide the HCP with the tools and strategies to deliver the TuiTek PSP and 2) a PSP Manual, consisting of A) a personalization screener, for HCPs to identify the key issues and challenges faced by patients and caregivers, and tailor the patient support; and B) a set of personalized one-to-one telephone call guides and resource packs which utilize a range of behavior change techniques (BCTs) and principles of MI, to support the HCP to engage in high-quality adherence-focused conversations with the patient during scheduled outbound calls with caregivers.

HCP-led calls which use BCTs and implement MI principles have been shown to affect meaningful behavior change across different health conditions such as increasing physical activity and improving diet,36,37 as well as demonstrating a positive impact on treatment adherence.38 This aligns with the findings of the TuiTek PSP which has been shown to positively address disease- and treatment-related barriers amongst caregivers regarding optimal adherence of their children to GH treatment; this, in turn, has the potential to improve adherence levels and patient clinical health outcomes.

Caregiver emotional distress has been found to be a driver of poor adherence and self-management skills in pediatrics and growth disorders.3941 This includes aspects related to anxiety and fear of the medication itself, but also aspects such as poor communication between parents and children. Overall, poor emotional wellbeing has a direct impact on the self-efficacy of both caregivers and patients themselves which ultimately will drive poor self-management behaviors.

There is a body of literature in pediatrics showing the efficacy of interventions to address the emotional wellbeing of caregivers of children living with chronic conditions. These include the use of techniques such as cognitive behavioral therapy and mindfulness.42,43 As a result, caregivers are better equipped to handle emotional stressors. Also, there is evidence of the positive impact of enhancing parenting skills such as communication to help cope with stressful situations related to the self-management of a chronic condition.44

In the CARING study, a digitally enabled intervention was designed and implemented to complement the work of the pediatric endocrinology unit in the University Hospital of Miguel Servet in Zaragoza, Spain.23 The clinicians identified children with suboptimal adherence using the easypod connect platform, their caregivers were then invited to participate in a study that includes the use of a digital program to deliver an intervention designed to improve the mental wellbeing of caregivers.

The digital intervention was powered by the ADHERA CARING platform that incorporates educational content to improve self-management skills, including gamification elements (eg quizzes), and is designed to ensure understandability and usability. This is complemented by content addressing mental-wellbeing based on cognitive behavioral therapy, including content such as videos of relaxation techniques aimed at helping families to reduce anxiety before injections. Furthermore, tailored motivational messages were sent to caregivers to reinforce engagement and therapeutic effectiveness. The behavioral design of the intervention was based on the Integrated Model for Behavioral Change (I-CHANGE).20

The first phase of the study included the recruitment of 10 caregivers who tested the program for a month and provided feedback in a semi-structured interview. The qualitative feedback data was used to identify areas for improvement and adjustment of the intervention prior to starting the second phase of the study which is aimed at quantifying the clinical impact of such an intervention. The preliminary results achieved in the first phase of the study showed high engagement and positive feedback; in addition, participants highlighted the importance of such interventions not only when adherence is suboptimal but also at the initiation of the treatment.23

There are several unmet clinical needs related to the management of a child with GHD. The first is the late age of diagnosis. In a recent study of 39 children with GHD, the mean age of diagnosis was 4.6 years in Germany, 7.0 years in the UK, and 9.4 years in the USA.45 The late age of diagnosis has a negative impact on the adult height achieved after r-hGH therapy.1 The subjects with abnormal variables are sent for investigation and diagnosis.46 Such a technique of height screening has not yet been demonstrated to work in a real-world busy inner-city environment.

A second unmet need relates to the poor quality of growth response to r-hGH therapy, for which there are a wide range of causes. Therapy needs to be individualized, in terms of starting dose, for every child starting therapy. The one-dose-fits-all philosophy which was widely practiced in the 1980s and 1990s can no longer be defended and is inconsistent with the current standards of precision medicine.47 Many children are receiving inadequate doses of r-hGH with a lack of sophisticated dose individualization taking into consideration the known predictive factors.48 In addition, GH responsiveness may be affected by influences outside the GH-IGF-1 axis such as genetic variants which can induce a degree of GH resistance.49 In these subjects, r-hGH therapy should logically be discontinued. The range of responses to r-hGH also extends to children with more severe GH deficiency, who respond well to r-hGH doses below the recommended dose. A third unmet need relates to patients displaying poor adherence to r-hGH therapy, as discussed in this article.

Finally, the standard of transitional care of the adolescent with GHD after completion of linear growth from pediatric to adult care is highly variable between centers and countries.50 Several digital tools are available to assess a young patients readiness for transition, including the Transition Readiness Assessment Questionnaire. This has been used in endocrinology to compare young people with Turner syndrome to those with type 1 diabetes, and revealed that those with Turner syndrome are less mature in the management of their healthcare and may find the process of transfer to adult services difficult.51 This aspect is, however, also connected with national healthcare policies. Mobile devices, such as smartphone apps (e.g. Tiny Medical Apps Digital Health Passport app), have been developed that can assist young people in self-managing their condition.

We believe that supporting patients across their disease journey means more than just providing them and their physicians with an effective therapy. Beyond the prescription of r-hGH, it means providing all stakeholders involved with the tools, information, services, and support needed to achieve the goal of effective treatment and clinical benefit. Methods for assessment of adherence need to be standardized, both from the point of view of definition of adherence and its measurement.52 For GH-deficient patients, caregivers, and HCPs, this has meant a change in the attitude towards r-hGH adherence and embracing the concept of a successful humandigital partnership which is essential to achieve these goals.2 The relationship between poor adherence and poor response to r-hGH therapy is well established.53 While enthusiasm and support for digital health technologies was slow at first, these efforts have accelerated with broader awareness and acceptance amongst both patients and HCPs. New digital technologies will evolve and the introduction of innovations and new technologies, while providing challenges for patients and HCPs, have the potential to further improve the personalized management of the GH-deficient patient receiving r-hGH therapy. The development of digital ecosystems reflecting the evolution of healthcare provision and an agile incremental approach of their enhancements by Iterative loops has the potential to improve disease management.

Editorial assistance was provided by Amy Evans of inScience Communications, Springer Healthcare Ltd, UK, and was funded by Merck Healthcare KGaA, Darmstadt, Germany.

This study was sponsored by Merck (CrossRef Funder ID: 10.13039/100009945).

MOS has consultancy agreements with Merck Healthcare KGaA Darmstadt and Pfizer as well as honoraria for lectures from Ipsen, GeneSciences, and Sandoz. LF-L is Chief Scientific Officer at Adhera Health Inc., Palo Alto, CA, USA. SG and PvD have consultancy agreements with Merck. MA has previously had a consultancy agreement with Merck. AdA does not have any conflicts of interest to declare. EK is an employee of Merck Healthcare KGaA, Darmstadt, Germany and holds shares in the company. The authors report no other conflicts of interest in this work.

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30. Tornincasa V, Dixon D, Le Masne Q, et al. Integrated digital health solutions in the management of growth disorders in pediatric patients receiving growth hormone therapy: a retrospective analysis. Front Endocrinol. 2022. doi:10.3389/fendo.2022.882192

31. Abdel-Tawab R, James DH, Fichtinger A, Clatworthy J, Horne R, Davies G. Development and validation of the Medication-Related Consultation Framework (MRCF). Patient Educ Couns. 2011;83(3):451457. doi:10.1016/j.pec.2011.05.005

32. Engel T, Ungar B, Ben-Haim G, Levhar N, Eliakim R, Ben-Horin S. Re-phrasing the question: a simple tool for evaluation of adherence to therapy in patients with inflammatory bowel disease. United European Gastroenterol J. 2017;5(6):880886. doi:10.1177/2050640616687838

33. Miller W, Rollnick S. Applications of Motivational Interviewing. 3rd ed. Guilford Press; 2012.

34. Weingarten SR, Henning JM, Badamgarav E, et al. Interventions used in disease management programmes for patients with chronic illness-which ones work? Meta-analysis of published reports. BMJ. 2002;325(7370):925. doi:10.1136/bmj.325.7370.925

35. Bennett HD, Coleman EA, Parry C, Bodenheimer T, Chen EH. Health coaching for patients with chronic illness. Fam Pract Manag. 2010;17(5):2429.

36. Cook PF, Emiliozzi S, El-Hajj D, McCabe MM. Telephone nurse counseling for medication adherence in ulcerative colitis: a preliminary study. Patient Educ Couns. 2010;81(2):182186. doi:10.1016/j.pec.2009.12.010

37. McBride CM, Rimer BK. Using the telephone to improve health behavior and health service delivery. Patient Educ Couns. 1999;37(1):318. doi:10.1016/S0738-3991(98)00098-6

38. Turner AP, Sloan AP, Kivlahan DR, Haselkorn JK. Telephone counseling and home telehealth monitoring to improve medication adherence: results of a pilot trial among individuals with multiple sclerosis. Rehabil Psychol. 2014;59(2):136146. doi:10.1037/a0036322

39. Silva N, Bullinger M, Sommer R, Rohenkohl A, Witt S, Quitmann J. Childrens psychosocial functioning and parents quality of life in paediatric short stature: the mediating role of caregiving stress. Clin Psychol Psychother. 2018;25(1):e107e118. doi:10.1002/cpp.2146

40. Gerain P, Zech E. Does informal caregiving lead to parental burnout? Comparing parents having (or not) children with mental and physical issues. Front Psychol. 2018;9:884. doi:10.3389/fpsyg.2018.00884

41. Alsaigh R, Coyne I. Mothers experiences of caring for children receiving growth hormone treatment. J Pediatr Nurs. 2019;49:e63e73. doi:10.1016/j.pedn.2019.09.005

42. Segal Z, Teasdale J, Williams J. Mindfulness-based cognitive therapy: theoretical rationale and empirical status. In: Hayes SC, Follette VM, Linehan MM, editors. Mindfulness and Acceptance: Expanding the Cognitive-Behavioral Tradition. Guilford Press; 2004:4565.

43. Townshend K, Jordan Z, Stephenson M, Tsey K. The effectiveness of mindful parenting programs in promoting parents and childrens wellbeing: a systematic review. JBI Database System Rev Implement Rep. 2016;14(3):139180. doi:10.11124/JBISRIR-2016-2314

44. Okafor M, Sarpong D, Ferguson A, Satcher D. Improving health outcomes of children through 10 effective parenting: model and methods. Int J Environ Res Public Health. 2014;11:296311. doi:10.3390/ijerph110100296

45. Brod M, Alolga SL, Beck JF, Wilkinson L, Hojbjerre L, Rasmussen MH. Understanding burden of illness for child growth hormone deficiency. Qual Life Res. 2017;26(7):16731686. doi:10.1007/s11136-017-1529-1

46. Savage MO, Backeljauw PF, Calzada R, et al. Early detection, referral, investigation, and diagnosis of children with growth disorders. Horm Res Paediatr. 2016;85(5):325332. doi:10.1159/000444525

47. Fernandez-Luque L, Al Herbish A, Al Shammari R, et al. digital health for supporting precision medicine in pediatric endocrine disorders: opportunities for improved patient care. Front Pediatr. 2021;9:715705. doi:10.3389/fped.2021.715705

48. Polak M, Konrad D, Tonnes Pedersen B, Puras G, Snajderova M. Still too little, too late? Ten years of growth hormone therapy baseline data from the NordiNet(R) international outcome study. J Pediatr Endocrinol Metab. 2018;31(5):521532. doi:10.1515/jpem-2017-0489

49. Argente J, Tatton-Brown K, Lehwalder D, Pfaffle R. Genetics of growth disorders-which patients require genetic testing? Front Endocrinol. 2019;10:602. doi:10.3389/fendo.2019.00602

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51. Culen C, Herle M, Ertl DA, et al. Less ready for adulthood?-Turner syndrome has an impact on transition readiness. Clin Endocrinol (Oxf). 2020;93(4):449455. doi:10.1111/cen.14293

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53. Loftus J, Miller BS, Parzynski CS, et al. Association of daily growth hormone injection adherence and height among children with growth hormone deficiency. Endocr Pract. 2022;28:565571. doi:10.1016/j.eprac.2022.02.013

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Cleveland Health Group Is Focused on Helping Men Eliminate Habit-Forming ED Medications with GAINSWave – Digital Journal

Posted: July 16, 2022 at 1:59 am

Independence, Ohio, United States 07-15-2022 (PR Distribution)

Cleveland Health Group, a world-class hormone replacement and anti-aging center located in Independence, OH, is offering a cutting-edge solution for men looking to overcome Erectile Dysfunction and Peyronies disease. The leading-edge treatment is known as GAINSWave, and the Cleveland Health Group is specifically treating patients with the Storz Medical Duolith Focused Device. The Storz Medical Duolith Focused Device is referred to as the most effective shockwave device in the market.

Cleveland Health Group focuses on providing patients with evidence-based solutions that negate the use of drugs, surgery or injections to treat the root cause of issues and ensure safe and long-lasting results. Unlike traditional medications that may lead to dependency and unwanted side-effects, GAINSWave utilizes extracorporeal shock wave therapy (ESWT) to naturally focus on treating the cause of ED instead of masking the symptoms. This non-invasive and drug free therapy uses high-frequency, low-intensity sound waves to improve blood flow to the penis, remove micro-plaque, and stimulate the growth of new blood vessels. GAINSWave is supported by over 50 medical studies, which show a greater than 75% success rate in treating ED.

We want to make sure that our patients receive the absolute best benefits from treatment. Thats why we specifically treat our patients with focused wave technology using the powerful Storz Medical Duolith Focused Device the latest and greatest in shockwave therapy for ED, shares Gabe Reider, founder of Cleveland Health Group. Weve successfully treated dozens of patients and are happy that we found a treatment option for ED that aligns with our quality standards, continues Reider.

In addition to using GAINSWave to optimize mens sexual health, the treatment can also be used in combination with platelet-rich plasma (PRP), Emsella and testosterone replacement, which provides men with a head-to-toe sexual health overhaul.

For a full list of conditions Cleveland Health Group can assist with, visit ClevelandHealthGroup.com or call 216-927-9900.

To learn more about new patient special offers, GAINSWave treatments or schedule an in-person consultation, visit ClevelandHealthGroup.com.

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At Cleveland Health Group, we provide unique, advanced treatment options that can help improve your health and wellness in the most natural way possible.

Say goodbye to habit-forming or stomach-upsetting pain medications. Do not be railroaded into a surgery you do not want or need especially with all the added risks and costs associated with it. Instead, let us help improve your health and wellness, naturally.

Media Contacts:

Company Name: Cleveland Health GroupFull Name: Gabriel ReiderPhone: 216-927-990Email Address: Send EmailWebsite: https://www.clevelandhealthgroup.com

For the original news story, please visit https://www.prdistribution.com/news/cleveland-health-group-is-focused-on-helping-men-eliminate-habit-forming-ed-medications-with-gainswave/9220358.

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Cleveland Health Group Is Focused on Helping Men Eliminate Habit-Forming ED Medications with GAINSWave - Digital Journal

Seth Feroce on Bodybuilders Using Gear: ‘Steroids Are Literally in Everything That Has to Do with Physicality’ Fitness Volt – Fitness Volt

Posted: July 16, 2022 at 1:59 am

Retired IFBB Pro Seth Feroce has become extremely vocal about sensitive issues affecting the sport of bodybuilding. In a recent truck rant video, Feroce says athletes from all professional sports are abusing steroids and voiced that theres corruption at every fuc**ng level.

Seth Feroce is by far one of the more outspoken voices present in bodybuilding. He led a successful career in the sport throughout the mid-2000s, battling against an array of top-level talent. While he hasnt competed in over a decade, Feroce is committed to the sport and seeing it improve. Over the past few months, steroids have become a controversial matter, which has prompted the community to speak on the concerning issue.

In 2021, an alarming number of bodybuilding deaths shook the world. In addition to former Mr. Olympia Shawn Rhoden passing away, George Peterson also met his untimely fate face-down in a hotel room before he had the chance to compete at 2021 Mr. Olympia.

The horrific trend continued this year as 29-year-old Bostin Loyd was pronounced dead back in March. Another death that sent shockwaves through the bodybuilding community was Cedric McMillan, who left behind his wife and kids at 44 years of age. For athletes like Feroce, these deaths arent a coincidence, and he continues to warn up-and-comers of the dangers that lie ahead should they pursue a professional career in bodybuilding.

Feroce says steroids will kill you and hes not the only bodybuilder issuing grave warnings about the harm they cause. Kali Muscle also addressed the matter, as he recently stated, if youre a bodybuilder, youre risking your life. According to Feroce, steroids are just as pervasive in other sports and hes astonished that people think other professional athletes arent cutting corners to get any edge they can for games/competitions.

In a recent video published on YouTube, Feroce says hes astonished that people dont recognize that corruption exists at every level in professional sports.

What I am fuc**ng astonished by, is the fact that people cant fuc**ing believe that professional athletes take steroids or theres no fuc**ing corruption. Are you guys fuc**ing with me? You know theres corruption at every fuc**ing level. Its a fuc**ing multi-billion dollar industry.

Im just astonished by the thought process. I dont know if its mainstream. How is this even a fuc**ing topic that people dont understand that steroids are literally in anything. In EVERYTHING that has to do with physicality, to gain a fuc**ing edge. Feroce said. Steroids are in fuc**ing everything and if you dont think so, you are a fuc**ing moron. You know why? Because I used to sell a lot of them. Seth Feroce said on Youtube.

Seth Feroce went on to say that he sold steroids to make ends meet during his career as an active IFBB Pro bodybuilder.

Thats something other bodybuilders say, I dont want to sell steroids. Bitch, I sold a shit load of them. How the fu** do you think I made ends meet as a competitor? You think I can just buy hundreds of pounds of meat? No. You either fuc**ing sold steroids, or you did gay for pay. I aint doing no gay for pay. Been offered many a times. But I rather fuc**ing sell a shit load of Tren and Anadrol and dick pills, like I did. Thats how the fuc**ing industry goes!

The retired Pro explained that its easy to get roped in to using steroids at a young age. He suggested over time that even the athletes who resist the compounds will eventually join the dark side once they start seeing results.

Then youre like fu** okay. Then, you kind of just get roped in, and you like it and then you think, maybe I should try it. Then you think youre going to get fuc**ing yoked from one fuc**ing cycle just like them, and that doesnt really happen. You gain some weight, and you get big, but you realize youre never going to be satisfied by it because you just get hooked in.

It happens and its happening right now because all of these young guys on the internet and young guys watching, Ill never go to the dark side. Bitch everybody is on the dark side. And everybody will go to the dark side.

After issuing several warnings, Feroce shared that nobody cares in professional sports whether someone uses steroids or not. He believes even when athletes die partly due to steroids, everyone in the community acts like they care, but really, they dont give a fu**.

At the end of the day, nobody actually gives a fu**. Nobody cares in professional sports whether you take steroids or not. Nobody fuc**ing cares in bodybuilding whether you take steroids or not.Nobody gives a fu**. Even whenever you take steroids and you fuc**ing die everybody acts like they give a fu** but nobody gives a fu**. Nobody fuc**ing cares. Do what you want to. Thats what Im getting at with this video. Dont be fuc**ing stupid. Stop believing in dumb shit, are you kidding me?

Feroce is convinced that multi-billion-dollar sporting leagues are fraught with corruption.

How do people not understand that in professional sports, like dude, were talking about multi-billion dollar industries. Multi-billion dollar industries. Billion dollar teams, just teams. One team worth fuc**ing three to four billion dollars. You think there is not some fuc*ed up covered up corruption going on? Youre out of your mind. Give me a break.

Back in April, Feroce revealed that hes been cutting out gear entirely, though mentioned that hes on a prescribed testosterone replacement therapy. While he has stepped away from the sport, Feroce always has unique opinions regarding bodybuilding.

The retired Pro believes the Mens Open division has taken a hit following COVID-19 since athletes arent traveling to other countries as often for shows like they used to. Feroce added that he believes the Mens Open division will fade into obscurity in the next five years.

RELATED: Bodybuilder Seth Feroce Reacts to Public Backlash After Killing a Black Bear: I Am Proud of This!

Feroce is confident that other athletes in varying professional sports abuse steroids to gain a competitive edge. After another truck rant, its evident Feroce wants to see a change in bodybuilding given his commitment to discussing these issues at length.

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Seth Feroce on Bodybuilders Using Gear: 'Steroids Are Literally in Everything That Has to Do with Physicality' Fitness Volt - Fitness Volt

The #1 Best Berry for Weight Loss, Says Dietitian Eat This Not That – Eat This, Not That

Posted: July 16, 2022 at 1:58 am

Summer is the season of berriesand there are so many to choose from to sprinkle on your morning granola, snack on midday, mix into a filling smoothie, or add to a fruit crisp. These small fruits pack a serious health punch.

"Berries are one of the most nutritional dense fruits," says Roxana Ehsani, MS, RD, CSSD, LDN, registered dietitian nutritionist and National Media Spokesperson for the Academy of Nutrition and Dietetics. "They are loaded not only with vitamins, minerals, and antioxidants but also with fiber!"

And if you're on a weight loss journey, they're an important fruit to have in your fridge. That's because berries really beat all other fruits when it comes to dietary fiber content.

"Fiber is one essential nutrient you need to include more of in your diet when you are looking to lose weight," explains Ehsani. "Berries provide feelings of fullness, as fiber-rich foods are digested at a slower rate than foods lower in fiber. This can help you from overeating at meal times and prevent you from reaching for more snacks throughout the day as well."

She adds that foods rich in dietary fiber like berries provide a slow release of energy into your bloodstream over time, which keeps your blood sugar more stable.

"More balanced blood sugar prevents falls or dips, which is also important when trying to lose weight," says Ehsani.

With that in mind, Ehsani says that the best berry to keep on hand if you're trying to lose weight is raspberries.

One cup of raspberries contains 65 calories, 15 grams of carbohydrates, 8 grams of dietary fiber, 5 grams of sugar, and 1.5 grams of protein.6254a4d1642c605c54bf1cab17d50f1e

"The reason raspberries are so high in dietary fiber is because the berry actually is composed of mainly little seeds," says Ehsani. "One cup of raspberries contains 53% of your daily value of vitamin C, helping you support your immune system at the same time!"

She adds that most of the carbohydrates in raspberries are coming from the fiber, making them a naturally low carbohydrate food, which can assist when trying to lose weight. And since one cup of berries is under 100 calories per cup, they're also a healthy low-calorie option when you're trying to lose weight.

"Eating nutrient-dense, low-calorie foods like raspberries can be the perfect substitute when you're craving something sweet, but looking for it not to pack too many calories," adds Ehsani. "You can eat more of the low-calorie food in place of the higher-calorie ones."

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Looking for ways to add more raspberries into your diet? Ehsani suggests you can add berries to your smoothies, smoothie bowls, and on top of chia seed pudding or yogurt.

"Add it to your ice cream bowl, on top of your piece of toast or waffle in the morning, and add them into your bowl of muesli or cereal or oats," she says.

Plus, you can make your own high-fiber jam (using fresh or frozen).

"Just mash your raspberries and mix with chia seeds and let sit. You will see the jam thicken as it sits, which you can then swirl into yogurt, spread on top of toast instead of regular jelly or jam," says Ehsani. "Blend frozen raspberries along with a frozen banana, and it turns into a creamy soft-serve like healthy fruity soft-serve ice cream alternative."

You could even add them to savory dishes! "Add berries to your grain and bean bowl or add them on top of a kale or spinach salad," Ehsani recommends.

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The #1 Best Berry for Weight Loss, Says Dietitian Eat This Not That - Eat This, Not That

Yoga for weight Loss: best yoga poses to burn fat and tone Up – Women’s Health UK

Posted: July 16, 2022 at 1:58 am

When you think of doing yoga for weight loss (or more likely fat loss, if we're getting technical), do you wonder whether it'll actually work or not? Because, if you do, you're not alone. Most of the time when people want to change their body composition thoughts of resistance training, burpees and cardio workouts spring to mind, not... chair pose, right? (To be clear, those are good ways of losing body fat, just maybe not the right choice for you, if you're a Yogi.)

Well, don't dismiss doing yoga for weight loss just yet. If finding your flow and practicing yoga stretches is one of the ways you like to move, it could be a great way to lose weight well, too. There's more nuance to how best to go about it, as well as myriad other benefits well beyond body composition and body fat percentage.

So, we've called upon the experts to dish the details on how to hit your health goals in the most zen way possible and answer your most frequently asked questions. Winning.

Note: Many yogis would argue that if you're using yoga purely for weight loss you're not connecting with the true purpose of the movement - a spiritual practice founded on ancient Indian wisdom.

Short answer, yes. Regular movement and being in a nutrient-focused calorie deficit is the key to healthy weight loss and yoga can absolutely play a part in that. However, it's a much more holistic process than just calories in calories out: 'It creates a deeper awareness of your physical and mental state, linking the breath to the movement of the poses (asanas),' explains yoga teacher Alexandra Baldi, founder of Compass Chelsea.

'This deeper awareness creates mindfulness and a greater intuition with your body, two key factors essential for weight loss; whether it's making healthier eating choices or knowing when to pull back to prevent too much cortisol in the body, a serious detriment to weight loss,' she says.

And the science backs Baldi up: The stress hormone cortisol can be a major inhibitor to weight loss, as shown by a 2016 study of overweight women, published in the American Journal of Managed Care. The research showed that restorative sessions, or Yin yoga, can produce the same weight loss results over 12-weeks as other forms of yoga.

But how? Well, by lowering cortisol levels by regularly unwinding through a consistent yoga practice, the women were able to successfully lose body fat.

Keen to calm down? This 9-move relaxing yoga flow oughta do the trick. Read what happened when WH Health Editor Claudia Canavan took on her own yoga challenge.

When it comes to how frequently you need to be getting down to your yoga mat, we're taking our lead from Fi Clarke, head of yoga at FLY LDN, whose approach takes into account actual real life. Hallelujah.

'If you're on a mission to lose weight it's best to thinking holistically about your lifestyle that includes stress levels, diet, alcohol consumption and work-life balance. Your yoga practice should be considered as a way to switch off, connect with yourself and give you time to gain headspace and perspective. Once your nervous system is soothed and cortisol levels are low, your body is in a much better position to organically lose weight.'

That cortisol word again, hey. Seems our nervous systems have a huge role to play in healthy and sustainable weight loss. But, if you're already in a place where you feel ready to incorporate regular movement into your life, what's a good benchmark to aim for?

'My suggestion would be to practice between 3-5 times a week and within that, incorporate at least one restorative yoga practice,' says Clarke. 'Try to ensure you're taking daily walks to help stay mobile and to give you time around nature, as this will also positively affect your mindset and nervous system, too.'

However, and this is good to remember depending on what type of yoga you're practising, your body's ability to endure it regularly will be different.

For example, if power or rocket yoga is your jam, you might only be able to hack two or three classes a week due to the intense nature of the sessions. Yin yoga, on the other hand, depending on time restraints, you could probably do every single day without feeling strung out, sore or knackered.

'Stronger practices require a tremendous amount of body strength and enable you to stretch and move your body in ways that develop stronger and more defined muscles as well as causing fatigue,' Baldi explains. 'So, for more intense styles, like Ashtanga or Power Yoga which burn greater amounts of calories I recommend three to four times a week.'

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According to Baldi, focusing on dynamic practices such as Ashtanga and Power Vinyasa will help you burn calories efficiently as you work towards your healthy body composition goals.

'Ashtanga yoga is a dynamic and physically demanding practice that follows a set sequence of 26 poses designed to purify the body by generating heat,' she explains. 'Power Vinyasa Flow on the other hand is a fast-moving practice that creates deep internal heat whilst paying close attention to proper alignment with thoughtful and creative sequencing. The continuous aerobic flow and pace of the practice are what creates more calorie burn.'

According to Nike Master Trainer and yoga-extraordinaire, Leah Kim, sun salutations are the best place to begin as they're novice-friendly and stimulate the entire cardiovascular system. Brilliant.

'Sun Salutations are cycles of flowing postures, and you can increase the intensity and number of cycles to increase the physical challenge. Just make sure youre breathing as youre moving,' she advises.

As there are so many different types of yoga, there isn't anyone specifically who shouldn't practice yoga. However, there might be some mitigating factors that help you decide what's best for you and your body.

'If you're pregnant or have recently given birth, it's important to practice specific pre/post-natal yoga that ensure your body isn't in any compromising positions,' advises Clark. 'If you're returning from an injury or operation or you suffer from a condition that affects your blood pressure, it's important to take it slowly with any exercise as your body needs time to adjust, so something like Yin would be advisable over a more powerful practice.'

From the outside, it may seem to be mindful breathing and pigeon pose but you can make some serious yogi-strength gains too. Chaturanga a key sequence in Vinyasa builds upper body and core strength with frequent planks and press-up movements, while downward dog puts your shoulders to the test and chair pose sets your glutes on fire.

Maintain mind to muscle connection and move with intention to really ramp up the muscle strength.

Making some time for yourself amongst everything going on in your life could be just the break you and your mental health need. From being a space to release suppressed emotions, let go of the day or calm your nervous system and stress response down, the mental clarity found on your yoga mat could be the thing to keep you feeling stable amidst stormy seas.

'Practising breath and breath with movement will soothe your nervous system. We all seem to be in a state of hyperarousal, so, to function at our optimal, we need to balance the active state with rest yoga will help you to do that, says yoga teacher and founder of The Human Method, Nahid de Belgeonne.

'Yoga cultivates your awareness and studies have shown again and again that when you are fully engaged in something you are more likely to enjoy higher levels of contentment; it also helps you to reduce stress and increase your feelings of wellbeing and that leads to better sleep.'

So, to feel calmer, more in control, sleep better and more deeply, think about incorporating some daily zen into your life.

Yoga can help with mobility issues, lengthening and loosening fascia and allowing you to sink more deeply into movements than you've ever been able to before. Mobility improvements will depend on which style you choose to practice but, as Clarke recommends, try and switch up your vigorous flows with more calming styles too.

'A regular yoga practice will pull you out of your habitual posture, giving you a lean silhouette,' says de Belgeonne.

'It strengthens your muscles and keeps your joints healthy and mobile. It also pulls your internal organs, nerve system, lymph system and connective tissue into multi-dimensions to keep them resilient and efficient.' Whole-body health and all down to a little movement every day. We're into it.

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Yoga for weight Loss: best yoga poses to burn fat and tone Up - Women's Health UK

UTSW researchers show effectiveness of migraine drug in weight loss – UT Southwestern

Posted: July 16, 2022 at 1:58 am

Chen Liu, Ph.D.

DALLAS July 11, 2022 Triptans, a commonly prescribed class of migraine drugs, may also be useful in treating obesity, a new study by scientists at UTSouthwestern suggests. In studies on obese mice, a daily dose of a triptan led animals to eat less food and lose weight over the course of a month, the team reported in the Journal of Experimental Medicine.

Weve shown that there is real potential to repurpose these drugs, which are already known to be safe, for appetite suppression and weight loss, said study leader Chen Liu, Ph.D., Assistant Professor of Internal Medicine and Neuroscience and an investigator in the Peter ODonnell Jr. Brain Institute.

Obesity affects more than 41% of all adults in the U.S. and increases the risk of heart disease, stroke, diabetes, and certain types of cancer. Most treatments for obesity focus on eating habits and physical activity.

Scientists have long known that serotonin, a chemical messenger found throughout the brain and body, plays a key role in appetite. However, there are 15 different serotonin receptors molecules that sense serotonin and signal for cells to change their behavior in response. Researchers have struggled to understand the role of each serotonin receptor in appetite, and previous drugs including fen-phen and lorcaserin (Belviq) that targeted certain individual receptors have been withdrawn from the market due to side effects.

Triptans, which are used to treat acute migraines and cluster headaches, work by targeting a different receptor the serotonin 1B receptor (Htr1b) that had not previously been well studied in the context of appetite and weight loss, said Dr. Liu.

For the new study, the researchers tested six prescription triptans in obese mice that were fed a high-fat diet for seven weeks. Mice fed two of these drugs ate about the same amount, but mice fed the other four ate less. After 24 days, mice given a daily dose of the drug frovatriptan lost, on average, 3.6% of their body weight, while mice not given a triptan gained an average of 5.1% of their body weight. Dr. Liu and his colleagues saw similar results when they implanted devices into the animals that gave them a steady dose of frovatriptan for 24 days.

We found that these drugs, and one in particular, can lower body weight and improve glucose metabolism in less than a month, which is pretty impressive, said Dr. Liu.

Since triptans are generally prescribed for short-term use during migraines, Dr. Liu suspects that patients would not have noticed the longer-term impacts on appetite and weight in the past.

To determine exactly how frovatriptan impacts food intake and weight, the researchers engineered mice to lack either Htr1b or Htr2c, the serotonin receptor targeted by fen-phen and lorcaserin. In mice without Htr1b, frovatriptan no longer could decrease appetite or cause weight loss, while cutting out Htr2c had no effect. This confirmed that the drug worked by targeting the serotonin 1B receptor.

This finding could be important for drug development, said Dr. Liu. We not only shed light on the potential to repurpose existing triptans but also brought attention to Htr1b as a candidate to treat obesity and regulate food intake.

The team went on to show exactly which neurons in the brain were most important for the role of Htr1b in mediating appetite, homing in on a small group of cells within the brains hypothalamus.

Other researchers who contributed to this study include Li Li, Steven C. Wyler, Luis A. Len-Mercado, Baijie Xu, Swati, Xiameng Chen, Rong Wan, and Amanda G. Arnold of UTSouthwestern; Youjin Oh and Jong-Woo Sohn of Korea Advanced Institute of Science and Technology; Lin Jia of UT Dallas; Guanlin Wang of the University of Oxford; Katherine Nautiyal of Dartmouth College; and Ren Hen of Columbia University.

The study was funded by the National Institutes of Health (R01 DK114036, DK130892, F32DK116427, K01AA024809), the American Health Association (16SDG27260001), a UTSW Pilot and Feasibility Award, and a Grossman Endowment Award for Excellence in Diabetes Research.

About UTSouthwestern Medical Center

UTSouthwestern, one of the nations premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

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UTSW researchers show effectiveness of migraine drug in weight loss - UT Southwestern

Novo Nordisk Hits Biocon With IP Suit Over Weight Loss Drug – Law360

Posted: July 16, 2022 at 1:58 am

By Jasmin Jackson (July 15, 2022, 6:55 PM EDT) -- Novo Nordisk has slapped competitor Biocon Pharma with a drug patent suit in Delaware federal court over a generic version of weight loss treatment Saxenda, contending that it's too soon for Biocon to pursue an off-brand alternative.

Novo Nordisk Inc. says in a complaint filed Thursday that Biocon Pharma Ltd. is attempting to manufacture a Saxenda generic before the expiration of Novo's 18 patents on the weight loss treatment that cover aspects of Saxenda's formulation and the injection device that distributes the drug.

According to the filing, Novo Nordisk still has market exclusivity until the asserted patents expire between 2024 and...

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Novo Nordisk Hits Biocon With IP Suit Over Weight Loss Drug - Law360

Leva’s Southern Charm is heightened by her incredible weight loss – Reality Titbit – Celebrity TV News

Posted: July 16, 2022 at 1:58 am

Leva Bonaparte from Bravos Southern Charm has always had striking looks. She has now had quite the effect on viewers after showing off her sudden weight loss during the latest season

Her appearance changed shortly after buying and moving into a new house with husband Lamar in an upscale neighborhood, a couple now seriously considering whether or not to have a second child.

Things havent just changed between Leva and her co-stars since season 8 she unfollowed Venita Aspen and Madison LeCroy after crews wrapped up but shes also brought a fresh new look to her appearance.

Leva revealed she had been putting weight on for years, which included when she was pregnant with her first child. She was inundated with messages from viewers asking about her appearance mainly pointing to her weight.

The Southern Charm star revealed she has always been a girl that generally watches what she eats, exercises and carried a hour glass shape figure but said different hormone treatments while getting pregnant caused weight gain.

She usually wore less revealing clothes but since losing weight, has been complimenting her new figure. And the change in her appearance was definitely not missed by Bravo fans!

Leva looks totally different in season 8 of Southern Charm, which was quickly noticed by viewers from episode 1. Her face looks noticeably thinner, which appears to emphasise her striking looks.

One fan wrote: Ok I need to know, what is up with Levas look? It is so totally different from last season, it cant just be weight loss, has to be more. Shes had something done for sure #SouthernCharm.

Another agreed, responding: Right? She looks stunning. Medically-enhanced BUT stunning.

It was at the beginning of 2021 when Leva decided to make a change to her lifestyle. As per Bravo, the reality TV star made a decision to seek out a plastic surgeon after her weight was at its highest ever.

The Southern Charm cast member revealed on Instagram that she had gained 70 pounds during her pregnancy with son Lamar Jr after years of putting on weight. Through lifestyle changes and exercise, she lost a good bit of weight.

Although she cut out carbohydrates and began doing cardio five times a week, Leva felt she still had some stubborn areas she couldnt lose, and therefore consulted a plastic surgeon to get some work done to tweak her body.

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Celine is a journalist with over five years of experience in the media industry and the chief staff writer on Reality Titbit. After graduating with a degree in Multimedia Journalism she became a radio newsreader and reporter, before moving into her current role as a reality TV writer.

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Modere Trim Review: Does it work for weight loss? – The Southern Maryland Chronicle

Posted: July 16, 2022 at 1:58 am

Modere Trim is an extremely popular weight loss supplement. It is arguably one of the most talked about weight management products on the market today, with all of the main fitness blogs publishing Modere Trim reviews in the last few months.

Modere Trim is also one of the only supplements promising to deliver both weight loss support, healthy skin and connective tissue health support. In other words, Modere Trim promises to make your skin look better, help you burn stored body fat, and help you recover from intense exercise.

But does Modere Trim really work as advertised?

What does Modere Trim actually do?

Is it the best supplement for body recomposition and weight loss you can buy right now?

In our comprehensive Modere Trim review below, we examine the weight support supplements ingredients, costs, side effects, and user reviews (as well as before and afters) to see if it really delivers on its promises.

Is Modere Trim Really Effective?

Modere Trim reviews confirm that it works. Modere Trim 2021 reviews also mention Modere Trims safety and effectiveness as weight loss supplements. Modere Trim promises a complete body transformation. It can restore your skins youthfulness, reduce fat, tone the muscles, and improve your gut health.

It reacts differently to different users. Some people notice the changes after one month while others take a while to see the results. Some people dont notice any changes. It might not work for everyone. You cant know if it will work for your situation until you test it.

#1 Modere Trim Alternative: LeanBean

SPOILER ALERT:We are not at all impressed with Modere Trim. As youll see from the ingredients section below, this weight loss supplement and youthful skin formula is a low quality weight loss aid and likely ineffective for improving body composition and giving you healthy skin.

The Liquid BioCell Collagen in Modere Trim is a gimmick, not a proven ingredient for weight loss or healthy skin. CLA is an effective weight loss supplement, but it doesnt do much by itself it doesnt boost metabolism or suppress appetite.

To really drive down body fat levels, you need to use several proven fat burners at once.

To make things even worse, Modere Trim lumps these ingredients and several more into a proprietary blend. This hides the individual serving sizes, meaning we dont know if theres even enough CLA in Modere Trim to do anything!

Thats why we recommend LeanBean instead.

LeanBean is a genuinely powerful weight loss supplement created specifically for women who need help curbing their appetite, increasing energy levels, and mobilizing stored fat from fat cells.

LeanBean combines 12 potent weight loss supplements proven by clinical trials to help you on your weight loss journey by suppressing appetite, accelerating metabolism and promoting lean body mass preservation.

LeanBean uses a 100% clean, transparent formula with no proprietary blends, no fillers, and a lot more power than CLA.

>>>CLICK THIS LINK FOR EXCLUSIVE DEALS AT LEANBEAN.COM<<<

#2 Rated Modere Trim Alternative: PhenQ

Another great option with far better benefits and much greater value for money than Modere Trim is PhenQ.

PhenQ is a pure weight loss supplement. Theres no gimmicky collagen or hyaluronic acid in here to give your skin a healthy glow. Instead, PhenQ was formulated as a natural alternative to phentermine, a potent weight loss aid and metabolism booster not available over the counter.

PhenQ uses natural ingredients to produce the same benefits as potent thermogenic fat burners without the same adverse effects.

The benefits of using PhenQ for several weeks include:

Unlike Modere Trim, PhenQ doesnt hide behind proprietary blends. Nor does PhenQ contain any obvious filler ingredients like Modere Trim does with CLA. Instead, we get a completely transparent formula and ingredients that have the backing of concrete evidence.

>>>CLICK HERE TO GET EXCLUSIVE DEALS FROM THE PHENQ WEBSITE<<<

Modere Trim Ingredients

Modere Trims popularity can largely be attributed to its ease of use and the extensive marketing efforts of the manufacturer. The liquid version of Modere Trim allows users to easily adjust their dosage with great granularity. But the blend of ingredients is not exactly cutting edge when it comes to accelerating weight loss.

The two main active ingredients in Modere Trim are Liquid Biocell and Conjugated Linoleic Acid, also known as CLA. Modere Trims makers claim that this combination produces a range of health benefits, including fat burning, reducing cellular fat storage, optimizing skin and muscle health, and muscle toning, but there is little evidence to support these claims.

Whats much worse than the ingredients themselves is the fact that Modere Trims ingredients are lumped into a 5g proprietary blend.

Studies showing increased fat mass metabolism and a decrease in fat cells in your body from CLA used 5g of that ingredient alone! Other ingredients include the unproven Garcinia Cambogia, the over-hyped Apple Cider Vinegar, and the totally useless gimmick of chicken sternum collagen, along with vegetable glycerine and potassium sorbate.

Proprietary blends are always a total rip-off. Heres a more detailed breakdown of Modere Trims ingredients.

Conjugated Linoleic Acid

Numerous studies have been done on CLA. There is a lot of solid evidence that using conjugated linoleic acid supplementation improves fat loss, although clinical trials dont show spectacular results.

Most studies have shown that CLA accelerates fat loss through a process called lipolysis, which essentially means the mobilization of stored fat for burning as fuel. A second observed mechanism is the reduction in fatty acid deposits in the bodys tissues.

While CLA is used in many fat burners (such as Night Shred), it isnt a very powerful fat burner. You have to take large quantities of CLA to see even slight improvements in weight loss; doses of 5g of either liquid form or powdered form of CLA are normal, with some people taking as much as 10g per day.

Modere Trims entire formula is just 5g in size. With Conjugated Linoleic Acid listed as the primary ingredient, we think it is highly likely that the Modere Trim proprietary blend is used as a screen to hide the fact that the formula is stuffed full of CLA, which is a cheap and widely available ingredient.

Liquid Biocell Chicken Cartilage

This ingredient is made from hydrolyzed chicken cartilage extract. This extract also contains chondroitin, hyaluronic acid, and collagen type 2 peptides. These ingredients can make your skin look youthful and glowing. These ingredients are said to improve your skins elasticity, and some of them are also said to support joint health.

One study that used hairless mice with Liquid Biocell revealed signs of photo-aging. There was a decrease in skin wrinkles and a rise in skin moisturization.

Although this study demonstrated the potential of Liquid Biocell in animals, human research has yet to confirm its effectiveness on human skin.

A clinical trialin which Biocell Collagen, BCC was tested on humans showed its effectiveness as an anti-aging treatment. The study involved 26 women who were given 1g of BCC for 12 weeks.

It optimized skin health by reducing skin wrinkles and dehydration. In just six weeks, there was an increase in collagen levels and hemoglobin. The increased blood flow can make the skin look younger, which can be a great thing for the skin.

Apple cider vinegar

Raspberry Ketones is another weight loss ingredient in the Modere Trim formula. This ingredient is very potent because it oxidizes fat cells in the body. This reduces fatty deposits in your liver.

This reduces liver toxicities that can lead to liver disease. Another benefit Modere Trim users receive from this component, which is an increase in energy.

Capsicum

CapsicumIs the main ingredient in bell peppers. This ingredient does a great job in boosting the bodys fat metabolism. Your body will burn fat more quickly if you have a higher metabolism. Capsicum can also help users control their eating habits, which is useful if they are trying to lose weight.

Garcinia Cambogia

Garcinia Cambogia is present in Modere Trim and helps to improve glucose production and lipid blood profiles. It also speeds up the bodys natural fat-burning process. This weight loss supplement can cause a reduction in body fat and overall weight.

If you take a closer look at these ingredients and the benefits they offer, it is clear that they can improve your overall health. One, a reduction in weight will improve your joint health. This is because it puts less pressure on your joints. You will also notice a noticeable improvement in skin appearance and muscle tone, as well as a decrease in fat storage.

The Modere Trim supplement is a positive addition to the human body that brings about fundamental changes.

Potential Modere Trim Side Effects

Will Modere Trim cause side effects?

Negative side effects from Modere Trim can vary from user to user. These are the most common potential side effects of Modere Trim:

Modere Trim side effects can be dangerous and you should immediately stop using the supplement.

How to Take Modere Trim

Modere Trim is recommended for beginners as one teaspoon per day. Modere Trim is best taken in the morning.

If your tolerance for the product has increased, you can increase the dosage. You should increase the dosage gradually and not use the weight management product too often.

What does Modere Trim Cost?

Is Modere Trim worth the money?

A single bottle of Modere trim is currently priced at $99.99 as of the writing of this article. Subscribe to a monthly delivery program and save 15% Modere Trim claims that 50% of Modere Trims claims are true, but this supplement would still be very expensive to use to shed a few pounds.

Other weight loss products offer faster fat burning and other health benefits.

Modere Trim Reviews, Complaints, Before & After Pictures

Any good Modere Trim review needs to look at other reviewsand customer complaints to make sure the product isnt getting slammed with hundreds of bad reviews!

There are quite a few bad reviews of Modere Trim on Trustpilot, although these are countered by far more extremely positive reviews. There arent many detailed user reviews posted on Reddit. The only place with a lot of Modere Trim reviews is Amazon but we know that these cannot really be trusted.

You may see some talk online of lawsuits being filed against Modere, or rumours that researchers have found a link between Modere Trim and cancer. As far as we are aware these are completely unfounded claims made by competitors.

Rather than looking for third-party Modere reviews, we recommend checking out Modere Trim before and after photos instead since these are harder (although not impossible) to fake.

Review Conclusion: Is Modere Trim the best weight loss supplement?

After doing a detailed Modere Trim review, we have to say that we have no idea how this fat burner became so popular. We think 99% of this dietary supplements popularity is down to marketing, because it certainly isnt due to its effectiveness.

Modere Trim only contains one active ingredient proven to help with weight loss in a human study, and thats CLA.

The other Modere Trim ingredients are more often found in joint health supplements rather than weight loss pills. But even then, we dont think consuming chicken sternal cartilage extract really helps your connective tissue health or your skin health.

If youre looking for a tried and true fat burner to help you get through your body transformation experience, we recommend using a professional weight loss stack combining effective appetite suppressants, thermogenic fat burners and lean muscle mass preservers in a clean, all-natural formula.

LeanBeancombines all of these qualities in a 100% natural formula free of the adverse side effects associated with cheap diet pills.

PhenQis another option for those that want a more intense fat loss supplement.

Modere Trim Frequently Asked Questions

How long does it take to see results from Modere Trim?

Some people see the effects of Modere Trim after a month, while others see them after a long while. Many users never see results.

Do you take Modere Trim before or after breakfast?

You should take Modere Trim in the morning preferably before eating anything.

Can I take Modere Trim twice a day?

There is no benefit to taking Modere Trim twice a day. The supplement is likely 90% CLA, and taking 8-10g isnt going to burn fat any faster than taking 4-5g.

Does collagen help you lose weight?

There is no evidence that collagen supplements help you lose weight.

Does Modere help with cellulite?

Modere claims that several of their supplements including Modere Trim help with cellulite. There is absolutely no evidence that any Modere products help with cellulite.

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Modere Trim Review: Does it work for weight loss? - The Southern Maryland Chronicle


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