Endocrine Care for Children with Prader-Willi Syndrome: 2025 Conference Insights

Understanding the endocrine system is essential for managing Prader-Willi syndrome (PWS). From infancy through adulthood, hormone-related challenges shape growth, development, metabolism, and overall health.

In this 2025 FPWR Conference presentation, Dr. Jennifer Miller, one of the world’s leading experts in pediatric endocrinology, explores the most pressing endocrine issues for individuals with PWS - and the evolving treatments that offer new hope for families.

Watch the full video below. If you’re short on time, use the timestamps below to jump to the sections that matter most to you.

Presentation Summary With Timestamps

00:00 Welcome by Kristi Rickenbach

Dr. Miller is a professor of pediatric endocrinology at the University of Florida and one of the world’s leading experts in Prader-Willi syndrome. She earned her MD from the University of Florida in 1998 and completed a master’s in clinical investigation in 2005.

She serves as the principal investigator on multiple clinical trials advancing treatment options for individuals with PWS and hypothalamic obesity, and currently follows several hundred individuals with PWS worldwide.

1:52 Disclosures

Dr. Miller has received research funding from Soleno Therapeutics, Rhythm Pharmaceuticals, Harmony Biosciences, and TRYP Therapeutics.

2:25 Agenda

• Endocrine Issues at Different Ages (infancy, childhood, adolescence, and adulthood)

• Cholesterol

• Diabetes

• Importance of Diet

• Vykat XR

• Other Clinical Trials

3:16 Growth Hormone in Infancy

• The average age of diagnosis of PWS in the U.S. is now 1.2 months.

• GH therapy has been shown to improve cognitive function (especially when started before age 1) and behavior in PWS.

• GH increases glucose levels (reducing hypoglycemia risk), which may be one way this therapy improves IQ.

• GH improves body composition (decreasing fat mass and increasing lean muscle mass) and enhances respiratory parameters.

• GH can shorten nutritional phase 1a (the period requiring assisted feeding), potentially reducing the need for G-tube placement.

4:22 Sleep Studies Pre- and Post-GH: Necessary or Not?

• GH is associated with sleep apnea in PWS due to the growth of tonsil and adenoid tissue.

• Dr. Miller does not recommend sleep studies for babies under 6 months, since tonsils and adenoids have not yet developed.

• If obstructive sleep apnea is present, it’s often due to low muscle tone (which GH improves). Central sleep apnea typically reflects brain immaturity. 

• Current guidelines: conduct a sleep study before starting GH, refer to ENT if sleep apnea is present, and delay GH if needed—but this approach is not ideal for all individuals.

• Parents concerned about monitoring can use pulse oximetry or the newly FDA-approved Owlet.

6:53 Thyroid Issues in Infancy

• Starting GH can unmask central hypothyroidism or central adrenal insufficiency as metabolism increases.

• Because the hypothalamus and pituitary form atypically in PWS, pituitary dysfunction is common.

• Approximately 20% of individuals with PWS will have central hypothyroidism, half soon after starting GH therapy, half starting around 18 months of age.

• Central hypothyroidism presents with normal/low TSH and low T4 (total and free).

• Monitor thyroid function every 6 months (Total and Free T4).

8:57 Hypogonadism in Infancy

• About 80% of individuals with PWS have hypogonadism (reduced function of the testes or ovaries).

• In males, cryptorchidism and hypogonadism can be treated with hCG therapy before 6 months to allow for the normal “mini-puberty” of infancy.

• hCG improves testicular function, increasing testosterone production and allowing testicular descent in about 30% of cases.

• No studies have yet evaluated hypogonadism treatment in female infants with PWS.

11:12 Adrenal Issues in Infancy

• The hormone cortisol helps keep your blood sugar normal, your blood pressure normal, and helps the immune response

  • The pituitary gland does not make enough adrenocorticotropic hormone (ACTH). When ACTH is too low, the adrenal glands do not make enough cortisol. This is also known as secondary adrenal insufficiency. 

  • The hypothalamus does not make enough corticotropin-releasing hormone (CRH). When CRH is too low the pituitary gland does not make enough ACTH. When ACTH is too low, the adrenal glands do not make enough cortisol. This is also known as tertiary adrenal insufficiency.

    Central adrenal insufficiency is caused by 1 of 2 things:

• Testing can yield false positives or negatives, so some doctors treat as if adrenal insufficiency is present with stress-dose steroids during illness or surgery.

13:49 Endocrine Issues in Childhood with PWS

• GH deficiency is typical; starting GH as early as possible (if diagnosis is after age 1) is recommended.

• Data shows that growth hormone at any age actually improves IQ.

• Central hypothyroidism affects ~20%, with average diagnosis at 18–24 months.

• Hypogonadism is common (~50%).

• Premature adrenarche (early pubic hair) occurs in 22–40% and is considered benign.

• Central adrenal insufficiency may affect up to 20% of children.

17:02 Lab Monitoring

• • Every 3–6 months (under age 3):
    IGF-1, IGFBP-3, Free/Total T4

  • Every 6 months (after age 3):
    IGF-1, IGFBP-3, Free/Total T4, liver/kidney function, CBC with diff, iron/ferritin, HbA1c, fasting cholesterol

  • If early puberty (before age 9):
    DHEAS (±17-OHP, testosterone, androstenedione), FSH/LH, estradiol or testosterone

18:30 PWS and GH Therapy

• IGF-1/IGFBP-3 levels typically rise after one year of GH therapy and often exceed normal ranges.

• Unless there’s overgrowth, this increase should not trigger a dose reduction.

• Recommendation: calculate the molar IGF-1/IGFBP-3 ratio to get "Free IGF1" levels (bioavailable IGF1) to determine best course of action for GH dosing

• It is impossible to determine tissue bioavailability and, thus, therapeutic efficacy or safety of GH dose from IGF1 or IGFBP-3 assays alone (which is why we do not rely on serum levels alone to determine GH dosing.)

23:01 Molar Ratio of IGF1/IGFBP-3

• Calculation of molar IGF1/IGFBP-3 ratio formula: IGF1 (ng/mL) x .13/[IGFBP-3 (ng/mL) x 0.035] = Free IGF-1

• The concentration of the bioactive free form of IGF1 does not increase on GH treatment, even if the total amount of IGF1 increases 

• See the video for a more detailed chart

23:46 Insulin Levels in Childhood and Growth Hormone

• High insulin increases IGF-1.

• Insulin levels rise between 15–18 months (nutritional phase 2a), especially in response to sweet tastes.

• Because individuals with PWS are more insulin-sensitive, high insulin promotes weight gain and craving for sweet foods.

• Increased interest/awareness of food begins around age 5 (nutritional phase 2b)
  
  
• See the video for a graph on insulin levels during different nutritional phases

25:13 Puberty Hormone Replacement

• Puberty often begins normally but fails to complete.

• Estrogen/testosterone replacement helps complete puberty and supports bone mineral density.

• Estrogen is replaced using the Turner syndrome protocol.

• Subcutaneous testosterone cypionate (25 mg weekly) is well tolerated by most males.

• hCG protocols are an option for adolescent males who prefer them to testosterone.

29:03 Important Endocrine Issues for Adults

• Lifelong monitoring and replacement of GH, thyroid, and sex hormones are vital.

• Low T3 levels are common in adults with PWS.

• Type 2 diabetes, high cholesterol, and hypertension become more frequent, requiring twice-yearly monitoring.

• Weight management can become more difficult as parental control of diet decreases.

30:41 Cholesterol

Individuals with PWS can have higher levels of total cholesterol and LDL cholesterol compared to others in family and even compared to obese controls. Possible causes include: 

• • Familial Hypercholesterolemia

  • Food restriction

    • During starvation, the body breaks down fat stores for energy. This leads to higher LDL cholesterol levels

    • Reduced cholesterol clearance due to low bile acids

    • Fiber is critical for clearance of cholesterol. Restriction of complex carbohydrates can lead to high cholesterol

  • Hypothyroidism

    • Thyroid hormone, like T3 and T4, help the body break down fats and remove cholesterol from the bloodstream

  • Low Vitamin D

    • Vitamin D may help reduce the absorption of cholesterol from the intestines

    • Also may help improve cholesterol breakdown in the blood

  • High insulin
    • Increases cholesterol production in liver
  • Low cortisol
    • Decreases cholesterol clearance from the blood

30:53 Diabetes

• Nearly all diabetes in PWS is Type 2.

• Risk for development of diabetes increases with age, degree of obesity, and insulin resistance

• Age of diagnosis of diabetes in PWS is 17.3 year (about 1/3 of the age on onset in the general population)

• Half of cases occur in children or teens.

• Because most people with PWS with diabetes are asymptomatic, up to 40% of cases are found incidentally on screening labs. Therefore, it is critical to monitor fasting blood work and HbA1c in individuals of all ages with PWS

32:39 Hyperphagia

• Hyperphagia is an extreme, unsatisfied drive to eat.

• May appear subtly or develop early.

• In nutritional phase 2b (ages 4–8), children begin asking for meals or snacks more often or repetitively.

• Severe restriction can worsen hyperphagia and lead to eating non-food items.

• Tracking BMI-Z score and weight/height helps distinguish hyperphagia from true hunger needs.

• See the video for a detailed graph on how individuals with PWS progress through various nutritional phases to go into hyperphagia.

35:15 Why do we say no sweet taste on a regular basis?

• The sight, smell, or taste of food triggers an early insulin response even before eating (the “cephalic” response).

• This insulin surge is much stronger in individuals with PWS.

• Sweet-taste receptors send signals to the hypothalamus, causing insulin release - leading to weight gain and increased calorie absorption.

37:37 Vykat XR and Other Clinical Trials

Vykat XR

• Reduces insulin release from pancreatic beta cells in response to food.

• Improves body composition, reduces anxiety and compulsive behaviors, and lowers fat mass.

• Hyperglycemia is a concern but is monitorable and manageable.

• In the Soleno Therapeutics program, patients with prior diabetes or insulin resistance were more likely to have blood sugar issues early on, but most were managed through dose adjustments or standard care.

• Regular fasting glucose or HbA1c monitoring is recommended.

Other Trials

• ARD-101 (Aardvark Therapeutics): activates bitter taste receptors in the gut to improve satiety and support weight loss. Phase 3 trial has started.

• Vagal Nerve Stimulation (VNS): FPWR-funded trial testing a non-invasive device to reduce temper outbursts. Early results show 4 of 5 participants improved after 9 months. Clinical trial (VNS4PWS) is currently enrolling participants with PWS (ages 10-40) who experience disruptive behaviors and temper outbursts. Participants will wear a tVNS device for 4 hours a day for 9 months

• Pitolisant (Wakix): FDA-approved for narcolepsy, now being studied for excessive daytime sleepiness (EDS) in PWS through the Phase 3 TEMPO trial.

• View the video for a detailed graph about the mechanism of action of all of these different trials. You can see these different drugs have multiple places that they can act in the brain. This gives us multiple different targets and opportunities

51:13 The Future

The future is really bright for individuals with PWS. However, this future depends on people keeping endocrinologic issues well treated, keeping diet healthy, maintaining regular physical activity, and education. 

51:31 Q&A

Watch Endocrine Care for Children with Prader-Willi Syndrome (2025 Conference Video) to view Dr. Miller’s full presentation and data from the 2025 FPWR Conference.