Search tips
Search criteria 


Logo of pchealthLink to Publisher's site
Paediatr Child Health. 2009 September; 14(7): 453–456.
PMCID: PMC2786952

Case 2: Hypoglycemia and micropenis in the newborn – hormonal red flags

Stacey Urbach, MD MPH FRCPC
Division of Endocrinology, The Hospital for Sick Children, Toronto, Ontario
Clodagh O’Gorman, MB BCh BAO MRCPI MSc
Division of Endocrinology, The Hospital for Sick Children, Toronto, Ontario
Dalia Alabdulrazzaq, MD BMBCh FAAP

At six months of age, a male infant was referred to the endocrinology clinic for investigation of a protruding tongue, suspected micropenis and abnormal thyroid function (increased thyroid-stimulating hormone level of 10.51 mU/L [normal 0.5 mU/L to 5 mU/L] and low free T4 level of 10 pmol/L [normal 10 pmol/L to 23 pmol/L]). He was born to a healthy primigravid woman by elective Caesarian section due to breech presentation, following an uncomplicated pregnancy. His mother took only prenatal supplements during the pregnancy. His birth weight was 3.23 kg (on the 25th percentile). On day 1 of life, he was transferred to the neonatal intensive care unit because of hypoglycemia. This required treatment with intravenous fluids, but the patient improved quickly and was discharged home on day 5 of life. Formal investigations for hypoglycemia were not performed. At two months of age, he was referred to a paediatrician for concerns regarding penile length and the presence of a protruding tongue. His examination was normal, except for a subjectively short penile length and tongue protrusion. The patient’s karyotype was reported as normal 46 XY.

When he was assessed in the paediatric endocrinology clinic, his weight and height were both on the 75th percentile. He was interactive but had a subjective ‘staring’ expression. His tongue appeared large for his mouth. His stretched penile length was 2.3 cm (mean [± SD] stretched penile length at term is 3.5±0.4 cm) and his penis was thin (mean circumference at term is 1.1±0.1 cm). The right testis was descended, and the left testis was retractile and palpated in the inguinal canal. He had no evidence of midline defects. Other systemic examinations were within normal limits. Further investigations revealed his diagnosis.


The patient’s pituitary assessement showed a low insulin-like growth factor of 31 ug/L (normal 48 ug/L to 350 ug/L), undetectable luteinizing hormone and follicle-stimulating hormone levels, low testosterone levels (lower than 0.2 nmol/L [normal 2.6 nmol/L to 13.9 nmol/L in males in the first seven months of life]), low random cortisol level of 33 nmol/L, sodium level of 134 mmol/L (normal 133 mmol/L to 142 mmol/L) and random urine-specific gravity lower than 1.005. He showed a suboptimal cortisol level at baseline of 68 nmol/L, and despite the use of a high-dose adrenocorticotropic hormone stimulation test (using 0.035 mg/kg synthetic adrenocorticotropic hormone), he had an inadequate 1 h stimulated level of 311 nmol/L (level expected to rise above 500 nmol/L after stimulation).

Repeat thyroid function tests showed a thyroid-stimulating hormone (TSH) level of 4.16 mU/L and a free T4 of 8.8 pmol/L. The inappropriately normal TSH level suggested a diagnosis of central hypothyroidism. The patient’s history of neonatal hypoglycemia with evidence of micropenis suggested growth hormone deficiency (GHD). Thus, he was diagnosed with panhypopituitarism including central hypothyroidism, probable GHD and central adrenal insufficiency. Although his urine was dilute with urine-specific gravity lower than 1.005, there was no history of polyuria or polydipsia and his serum sodium level was normal. This was not suggestive of diabetes insipidus. He was commenced on oral hydrocortisone for central adrenal insufficiency followed by L-thyroxine for hypothyroidism. Hydrocortisone was initiated first to prevent an adrenal crisis that may theoretically occur with initiation of thyroid hormone in a patient with adrenal insufficiency. He also received a three-month course of monthly testosterone injections to increase his penile length. GH testing was not performed initially because of good growth parameters. However, GH was initiated after the patient was noted to be hypoglycemic during an intercurrent illness.

A magnetic resonance imaging (MRI) scan of his brain showed structural pituitary abnormalities including an ectopic posterior pituitary and a small pituitary stalk. He is presently one year and nine months of age and has required a number of admissions to hospital during times of illness. His growth and development have been normal and will be followed closely, along with monitoring for the development of diabetes insipidus. He will require a full evaluation of his hypothalamic-pituitary-gonadal axis when he approaches the age of puberty, and further testosterone therapy will likely be needed.

The thyroid hormone is important for normal development of the central nervous system, particularly during fetal development and the first two years of life. Children with untreated congenital hypothyroidism are at risk for impaired cognitive and motor development. Hypothyroidism can be due to thyroid disease (primary hypothyroidism) or due to a disorder of the hypothalamic-pituitary axis. The classical teaching is that central hypothyroidism manifests as low TSH with low T4. However, in reality, in central hypothyroidism, serum free T4 is low, but serum TSH may initially be low, normal or even slightly elevated. In one study (1) of patients with central hypothyroidism, 35% of patients had undetectable serum TSH concentrations, 41% had normal values and 25% had high values. Many patients with central hypothyroidism have coexisting deficiencies in other pituitary hormones.

The history of neonatal hypoglycemia in a patient referred for hypothyroidism and micropenis was very important. Hypoglycemia is a common neonatal problem. However, persistent, resistant or recurrent hypoglycemia should alert the physician to other possible etiologies, including hormonal deficiencies. GHD is a known cause of hypoglycemia. GH promotes the lysis of fats, which releases the gluconeogenic compound, glycerol. GH also has anti-insulin actions, which block the diversion of blood glucose to muscle, fat or other insulin-sensitive organs, thus helping to maintain adequate glucose in the circulation. Thus, GH deficiency may lead to hypoglycemia, particularly in infants with poor substrate stores.

Congenital GH deficiency does not affect fetal growth. In the fetus, growth is influenced by genetic and environmental factors, as well as by nutrition and growth factors, including insulin. The first two years of life represent a transition period when growth changes from predominantly GH independent to GH dependent. Therefore, newborns with GHD are born with normal weight and length, and later, postnatal growth failure occurs.

Neonatal hypopituitarism may also manifest with micro-penis in boys, caused by either GHD or gonadotrophin deficiency. Penile size is measured from the pubic tubercle to the tip of the stretched penis, and micropenis is defined as stretched penile length less than 2.5 cm (2). The definition of normal penile size may vary according to ethnicity (3). In 2004, the National Cooperative Growth Study (4) database of children on GH therapy included 41,283 children, of whom 169 (100 male and 69 female) were started on GH for the treatment of neonatal hypoglycemia. Of these 169 patients, 148 had hypopituitarism, 12 had isolated GH deficiency and nine had no hypothalamic or pituitary dysfunction. More than 30% of the patients had structural lesions of the hypothalamic-pituitary area or midline facial defects, and more than 50% of the males had micropenis. Multiple hormone replacement therapies were necessary in 89% of these hypoglycemic infants (4). Once one pituitary hormone is found to be deficient in a patient, he or she should be evaluated for the presence of other pituitary hormone deficits.

Once one or more pituitary hormone deficits are diagnosed, an MRI of the hypothalamic-pituitary area should be performed to look for structural abnormalities. The most common abnormality is the triad of a small anterior pituitary gland, hypoplastic pituitary stalk and ectopic posterior pituitary. In one study (5), pituitary abnormalities detected by MRI were common in those with isolated GH deficiency (80%) and those with multiple pituitary hormone deficiencies (93%). An MRI is also helpful in the prediction of permanent GHD, because children with congenital hypothalamic-pituitary abnormalities on MRI scans are more likely to have life-long GH deficiency.

Early recognition of pituitary defects causing hypothyroidism and/or hypoglycemia is essential. Untreated, these may lead to irreversible developmental delay and disability. Most children with isolated GHD have normal development (2) and can attain final adult height within the range for their family, if therapy is instituted early.


  • Central hypothyroidism may manifest with low, normal or high TSH levels.
  • Always look for GHD in any infant who presents with recurrent, persistent or severe neonatal hypoglycemia.
  • The presence of micropenis can be a simple diagnostic clue to GHD.
  • The presence of one pituitary hormone deficit should lead to a thorough assessment of the hypothalamic-pituitary-adrenal axis to rule out other deficiencies.
  • An MRI of the hypothalamic-pituitary-adrenal axis should always be performed to look for structural causes of hypopituitarism.
  • Further pituitary hormone deficiencies can evolve over time; thus, long-term follow-up with regular hormonal re-evaluation is required.


1. Faglia G, Bitensky L, Pinchera A, et al. Thyrotropin secretion in patients with central hypothyroidism: Evidence for reduced biologic activity of immunoreactive thyrotropin. J Clin Endocrinol Metab. 1979;48:989. [PubMed]
2. Ludwig G. Micropenis and apparent micropenis – a diagnostic and therapeutic challenge. Andrologia. 1999;31(Suppl 1):27–30. [PubMed]
3. Cheng PK, Chanoine JP. Should the definition of micropenis vary according to ethnicity? Horm Res. 2001;55:278–81. [PubMed]
4. Bell JJ, August GP, Blethen SL, et al. Neonatal hypoglycemia in a growth hormone registry: Incidence and pathogenesis. J Pediatr Endocrinol Metab. 2004;17:629–35. [PubMed]
5. Hamilton J, Blaser S, Daneman D. MR imaging in idiopathic growth hormone deficiency. AJR AM Neuroradiol. 1998;19:1609–15. [PubMed]

Articles from Paediatrics & Child Health are provided here courtesy of Pulsus Group