Low Growth Hormone Symptoms: Drugs That Cause or Treat It

What Are the Symptoms of Low Growth Hormone?

Growth hormone deficiency produces overlapping physical and metabolic changes that are easy to miss because each symptom can be explained by other common conditions. The 2011 Endocrine Society Clinical Practice Guideline on adult GHD describes the phenotype as "increased fat mass, reduced lean body mass, decreased bone mineral density, and impaired quality of life" as the core features clinicians should recognize [1].

Physical and Body-Composition Changes

In adults, the most consistent finding is a shift toward visceral adiposity. A meta-analysis of 10 randomized controlled trials published in the Journal of Clinical Endocrinology and Metabolism reported that adults with confirmed GHD carried an average 4.5 kg more fat mass than age-matched controls [2]. Muscle mass and grip strength decline in parallel, and patients often describe this as unexplained weakness rather than outright pain.

Skin texture changes, including thinning and reduced elasticity, also appear in GHD. These are driven by the loss of GH's direct effects on dermal collagen synthesis. Bone mineral density (BMD) falls over years, raising fracture risk even before osteoporosis criteria are met on DEXA scanning.

Metabolic and Cardiovascular Findings

Adults with GHD show elevated LDL cholesterol, reduced HDL cholesterol, and higher triglycerides. Carotid intima-media thickness is measurably greater in untreated GHD patients compared to controls, per a study in Atherosclerosis (N=118, P<0.01) [3]. Insulin resistance is common, though frank diabetes is not inevitable.

Neuropsychological Symptoms

Fatigue is the symptom patients most frequently report first. Cognitive complaints, specifically difficulties with memory and concentration, appear in validated questionnaires. The Quality of Life-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) scale captures these dimensions; mean scores in untreated GHD patients average 11 to 14 out of 25, where higher scores indicate worse quality of life [4].

Pediatric-Specific Features

Children present differently. Short stature (height velocity below the 25th percentile for age) is the primary concern. A peak GH response below 10 µg/L on stimulation testing is the standard diagnostic threshold in pediatric guidelines from the Growth Hormone Research Society [5]. Delayed bone age, increased subcutaneous fat with preserved or reduced muscle, and delayed puberty round out the pediatric picture.

What Causes Low Growth Hormone?

GH deficiency has structural, iatrogenic, and functional causes. Clinicians distinguish between organic GHD (identifiable pituitary or hypothalamic pathology) and idiopathic GHD, which is more common in children.

Pituitary and Hypothalamic Pathology

Pituitary adenomas and their treatment account for the largest proportion of adult-onset organic GHD. Craniopharyngioma is the most common pituitary-region tumor causing GHD in children. Traumatic brain injury (TBI) is an under-recognized cause: a systematic review in Pituitary journal (N=1,137 TBI patients) found GHD in approximately 10 to 20% of survivors at 12-month follow-up [6].

Radiation therapy to the brain or skull base predictably damages the hypothalamic-pituitary axis. GH is the most radiation-sensitive anterior pituitary hormone; deficiency can appear with doses as low as 18 Gy delivered to the hypothalamus [7].

Functional GH Suppression (Non-Structural)

Obesity itself suppresses GH pulse amplitude through somatostatin excess. Hypothyroidism and uncontrolled diabetes also blunt GH secretion. These functional causes produce low IGF-1 and blunted GH stimulation tests without structural pituitary damage, which matters because treating the underlying cause often normalizes GH without hormone replacement.

Genetic and Congenital Causes

Mutations in GHRHR, GH1, POU1F1, PROP1, and LHX3 genes cause isolated or combined pituitary hormone deficiencies. Septo-optic dysplasia accounts for a subset of congenital cases.

Drugs That Cause Low Growth Hormone

Several widely prescribed medications suppress GH secretion either directly or by altering hypothalamic signaling. Recognizing these is clinically meaningful because stopping or replacing the offending agent may resolve GH suppression without initiating hormone therapy.

Glucocorticoids

Glucocorticoids are the most clinically significant pharmacological suppressors of GH. They reduce hypothalamic GHRH release, increase somatostatin tone, and directly impair pituitary GH secretion. A controlled study in the Journal of Clinical Endocrinology and Metabolism showed that prednisolone 5 mg daily for 12 weeks reduced mean IGF-1 by 28% in healthy adults [8]. Inhaled corticosteroids at high doses (fluticasone 1,000 µg/day or equivalent) produce measurable HPA-axis and GH-axis suppression in children, though the effect is smaller than systemic use.

Opioids

Long-term opioid therapy suppresses the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-GH axes. A cross-sectional analysis of 50 men on chronic intrathecal opioids found GHD in 15 of 50 subjects (30%) on formal stimulation testing [9]. The mechanism involves opioid receptor-mediated inhibition of GHRH neurons. Methadone and morphine appear to carry higher risk than buprenorphine in available data, though comparative trials are limited.

Oral Estrogens

Oral estrogen formulations (not transdermal) reduce hepatic IGF-1 production through first-pass metabolism. Women taking oral combined oral contraceptives or oral estradiol for menopause show IGF-1 levels 25 to 35% lower than women using transdermal estradiol at equivalent systemic doses [10]. This matters because oral estrogen can mask GHD (by lowering IGF-1 independently) or can make GH replacement less effective by blunting hepatic IGF-1 response. Switching from oral to transdermal estradiol often requires upward dose adjustment of GH replacement.

Dopamine Antagonists

Dopamine normally stimulates GH release. Antipsychotic medications that block dopamine receptors (haloperidol, risperidone, olanzapine) blunt GH pulse amplitude. The effect is modest in healthy subjects but clinically significant in patients already on the borderline of GH sufficiency.

Other Agents Worth Noting

Somatostatin analogues (octreotide, lanreotide) used for acromegaly or neuroendocrine tumors directly suppress GH secretion. Pegvisomant, a GH receptor antagonist used in acromegaly, does not suppress GH secretion but blocks its action, producing a functional GHD state. High-dose testosterone in supraphysiological ranges (as seen in anabolic steroid misuse) may paradoxically suppress the pituitary GH axis via negative IGF-1 feedback.

How Is Growth Hormone Deficiency Diagnosed?

A single random GH level is essentially useless for diagnosing GHD because GH is secreted in pulses and is undetectable for most of the day. IGF-1 is the best screening marker because it reflects integrated 24-hour GH exposure. However, IGF-1 has limited sensitivity: roughly 30 to 40% of adults with confirmed GHD have IGF-1 within the age-adjusted reference range [1].

Stimulation Testing

The insulin tolerance test (ITT) is the reference standard. A symptomatic hypoglycemia (blood glucose <2.2 mmol/L or 40 mg/dL) is required for the test to be interpretable. A peak GH below 3 µg/L during ITT confirms GHD in adults by Endocrine Society criteria. The test is contraindicated in patients with seizure disorders, ischemic heart disease, or age above 65 years.

The GHRH-arginine test is the preferred alternative when ITT is contraindicated. Cut-points are BMI-adjusted: peak GH <11 µg/L in patients with BMI <25 kg/m², <8 µg/L for BMI 25 to 30 kg/m², and <4 µg/L for BMI above 30 kg/m² [1]. Glucagon stimulation testing is a second alternative, particularly relevant after GHRH analogue (tesamorelin) supply concerns limit GHRH-arginine availability.

When Three or More Pituitary Hormone Deficiencies Coexist

The Endocrine Society guideline states: "When three or more other pituitary hormone deficiencies are present and the IGF-1 level is low, we suggest that GH stimulation testing is not necessary for the diagnosis of GHD" [1]. This pragmatic exception reduces unnecessary testing burden in patients with known destructive pituitary pathology.

Treatments for Low Growth Hormone

Recombinant Human Growth Hormone (Somatropin)

FDA-approved recombinant human GH (rhGH, somatropin) is the standard treatment for both adult and pediatric GHD. Available branded formulations include Norditropin (Novo Nordisk), Genotropin (Pfizer), Humatrope (Lilly), Saizen (Merck Serono), Nutropin AQ (Genentech), and Omnitrope (Sandoz, the first FDA-approved GH biosimilar) [11].

Adult dosing starts low. The Endocrine Society recommends beginning at 0.2 mg/day subcutaneously in younger adults and 0.1 mg/day in older adults or those with diabetes, then titrating every 4 to 8 weeks guided by serum IGF-1, clinical response, and side effects [1]. Weight-based dosing (used historically in pediatrics) is not recommended in adults because it leads to more adverse effects without better outcomes.

Pediatric Dosing

In children, dosing is weight-based: the typical range is 0.16 to 0.24 mg/kg/week given as daily subcutaneous injections. Prader-Willi syndrome, Turner syndrome, SGA, and chronic renal insufficiency have specific FDA-approved pediatric GH indications with distinct dosing ranges. The Pfizer-sponsored GeNeSIS registry (N=18,028 pediatric patients) documented mean first-year height velocity increase of 3.5 cm/year above pre-treatment baseline in GHD children on Genotropin [12].

Adverse Effects of Somatropin

Common early adverse effects include fluid retention (peripheral edema), arthralgias, and myalgias. These are dose-related and usually resolve with dose reduction. Carpal tunnel syndrome affects roughly 2% of adults on GH therapy. GH therapy is contraindicated in active malignancy, diabetic retinopathy, closed epiphyses in children seeking height gain, and critical illness.

GH-Releasing Agents

Two classes of GH-releasing agents are used clinically.

Sermorelin (GHRH 1-29 analogue) stimulates endogenous GH release from the pituitary. It was FDA-approved for pediatric GHD but the branded product (Geref) was voluntarily withdrawn from the US market in 2008; it remains available through compounding pharmacies. Because it stimulates native pulsatile GH release rather than providing exogenous GH, sermorelin has theoretical advantages in preserving physiological GH pulsatility. Controlled trial data in adults with GHD are limited compared to somatropin.

Tesamorelin (Egrifta, Theratechnologies) is a stabilized GHRH analogue with a single FDA-approved indication: reduction of excess visceral adipose tissue in HIV-infected adults with lipodystrophy. In the LIPO-010 trial (N=412), tesamorelin 2 mg/day reduced visceral fat by 18% versus 2% with placebo at 26 weeks (P<0.001) [13]. It is not FDA-approved for non-HIV GHD but is sometimes used off-label.

GH secretagogues and ghrelin mimetics include ibutamoren (MK-677) and other compounds under investigation. None are FDA-approved for GHD as of the publication date of this article.

Tesamorelin vs. Somatropin: Practical Differences

| Feature | Somatropin | Tesamorelin | |---|---|---| | FDA indication in GHD | Yes (adult and pediatric) | No (HIV lipodystrophy only) | | Mechanism | Direct GH replacement | GHRH receptor agonist | | Effect on IGF-1 | Directly raises IGF-1 | Raises IGF-1 via pituitary GH | | Route | Subcutaneous daily | Subcutaneous daily | | BMD improvement | Documented in RCTs | Not established in GHD |

Monitoring Growth Hormone Therapy

IGF-1 is the primary monitoring biomarker. The target during adult GH replacement is an IGF-1 in the mid-normal range for age and sex, roughly the 50th percentile of the age-matched reference interval. Measuring IGF-1 every 4 to 8 weeks during dose titration and every 6 months once stable is recommended by the Endocrine Society [1].

Metabolic and Bone Monitoring

Fasting glucose and HbA1c should be checked before starting and annually during treatment, because GH has anti-insulin effects. DEXA scanning at baseline and every 1 to 2 years quantifies BMD response. Lipid panel improvements (reduced LDL, raised HDL) typically emerge within 6 to 12 months of adequate GH replacement.

Children: Growth Velocity and Bone Age

In pediatric patients, height velocity (cm/year) is the primary efficacy endpoint. Bone age X-rays (left hand and wrist) are obtained annually to ensure epiphyseal plates remain open. Treatment continues until final height is achieved or growth velocity falls below 2 to 2.5 cm/year with open epiphyses.

Transitioning from Pediatric to Adult GH Care

Adolescents with childhood-onset GHD require re-testing after epiphyseal fusion if the original GHD was idiopathic or isolated. Endocrine Society guidance recommends a washout of at least one month followed by an ITT or GHRH-arginine test. Those with confirmed organic GHD (structural lesion, multiple pituitary hormone deficiencies) generally do not require re-testing [1].

When Should You Worry? Red Flags Requiring Prompt Evaluation

Most GHD symptoms develop slowly over months to years. A few presentations warrant faster workup.

Rapid-onset severe fatigue combined with central adiposity gain and new dyslipidemia after pituitary surgery or cranial radiation should trigger GH axis testing within 3 to 6 months of the event. Children with height velocity below the 5th percentile for age for two consecutive 6-month periods need formal GH evaluation without further delay. Adults reporting cognitive decline after TBI who also have low IGF-1 should be referred for endocrine assessment because TBI-related GHD is treatable.

A measured serum IGF-1 below the age-sex-adjusted 2.5th percentile in a symptomatic patient is enough to proceed to stimulation testing even before other pituitary hormones are checked.