Calcitriol and Levothyroxine Dosing for Patients With Pseudohypoparathyroidism

Jacqueline Antoun; Dylan Williamson; Merla Hubler; Ashley H. Shoemaker


J Endo Soc. 2021;5(12) 

In This Article

Abstract and Introduction


Pseudohypoparathyroidism (PHP) is a rare hormone resistance syndrome caused by mutations in GNAS. This cross-sectional study investigated whether PHP patients with parathyroid hormone (PTH), thyrotropin (thyroid stimulating hormone; TSH), and free thyroxine (T4) levels at goal required higher doses of levothyroxine and calcitriol than recommended by current guidelines to overcome mineral ion abnormalities due to hormone resistance.

Baseline demographic and clinical data of participants enrolled in PHP research studies between 2012–2021 were collected via retrospective chart review. Longitudinally, data were recorded at a maximum frequency of once a year starting at 1 year of age. The PTH at goal (PAG) group was defined as PTH < 150 pg/mL and calcium ≥ 8.4 mg/dL, and the TSH and free T4 at goal (TAG) group was defined as TSH < 5 mIU/L and free T4 ≥ 0.8 ng/dL.

The PAG group (n = 74) was prescribed higher calcitriol doses than the PTH not at goal (PNAG) group (n = 50) (0.9 ± 1.1 vs 0.5 ± 0.9 mcg/day, P = 0.04) and 21% of individual patients were prescribed ≥ 1.5 mcg of calcitriol daily. This remained true after normalization for body weight (0.013 ± 0.015 vs 0.0067 ± 0.0095 mcg/kg/day, P = 0.008). There was no statistically significant difference in levothyroxine dosing between the TAG group (n = 122) and TSH and free T4 not at goal (TNAG) group (n = 45) when normalized for weight (2.0 ± 0.7 vs 1.8 ± 0.7 mcg/kg/day, P = 0.2).

More than one-third of patients with PHP had PTH levels not at goal and some patients required calcitriol doses ≥ 1.5 mcg/day to meet current treatment goals.


Pseudohypoparathyroidism (PHP) is a rare hormone resistance syndrome caused by mutations in the GNAS gene which encodes the α subunit of the stimulatory G-protein (Gsα).[1,2] Pseudohypoparathyroidism type 1a (PHP1A) is caused by loss of function mutations on the maternal GNAS allele. Lack of normal Gsα expression results in abnormal G-protein coupled receptor (GPCR) function. The resulting phenotype occurs due to disruptions in the Gsα-mediated cyclic AMP second messenger signaling pathway which is utilized for many hormones, including parathyroid hormone (PTH) and thyrotropin (thyroid stimulating hormone; TSH) but also luteinizing hormone, follicle-stimulating hormone, and growth hormone–releasing hormone. Due to tissue specific imprinting of GNAS in regions such as the pituitary, thyroid, gonads, renal proximal tubules, and hypothalamus, patients with PHP1A have significantly reduced G-protein coupled receptor function, leading to multi-hormone resistance.[3–5] Abnormal methylation of GNAS, referred to as type 1b (PHP1B), also causes abnormal Gsα expression and clinically significant hormone resistance.[6]

The most common forms of hormone resistance in PHP are resistance to PTH and TSH.[7] TSH resistance is often present at birth and can be identified on newborn screening tests, often requiring relatively low and stable levothyroxine supplementation.[1] In contrast, there is postnatal reduction of the paternal Gsα expression in the proximal renal tubules.[1,8] PTH resistance typically presents post-infancy with an asymptomatic increase in PTH that if untreated progresses to hypocalcemia. Historically, PTH resistance was treated according to hypoparathyroidism guidelines with calcitriol doses titrated to achieve low-normal calcium levels for fear of overtreatment leading to urine hypercalcemia and subsequently nephrocalcinosis. However, a 2012 report of 5 cases of tertiary hyperparathyroidism in adults with PHP1B raised concern that prolonged exposure to high PTH levels can itself have deleterious effects such as tertiary hyperparathyroidism and hyperparathyroid bone disease.[9] In addition, patients with PHP are at lower risk of renal complication due to preserved anticalciuric effects of PTH on the distal renal tubules.[10] Recent international treatment guidelines now recommend maintaining calcium levels that are on the upper end of normal or slightly elevated to sustain PTH-dependent calcium reabsorption in the distal convoluted tubules.[11,12]

To overcome mineral ion abnormalities due to intrinsic hormone resistance, high medication doses may be required. There are no published dosing guidelines for levothyroxine or calcitriol in patients with PHP, and physicians may be hesitant to prescribe medication doses outside the typical range for hypoparathyroidism and hypothyroidism. To better understand the natural history of hormone resistance in PHP and the range of medication dose requirements, we undertook a retrospective chart review of patients in our PHP research database.