1.1 Hypopituitarism

Suggested citation: The Endocrine Society. Endocrine Facts and Figures: Hypothalamic-Pituitary. First Edition. 2016.

Hypopituitarism, whether congenital or acquired, refers to the complete or partial deficit of anterior and/or posterior pituitary hormones.1 While congenital hypopituitarism occurs due to the abnormal prenatal development of either the pituitary or hypothalamus, acquired hypopituitarism may occur either due to or as a response to the treatment of pituitary, non-pituitary, or hypothalamic tumors (i.e. surgery and radiation therapy); traumatic brain injury; subarachnoid hemorrhage; and autoimmune conditions.2

1.1.1 Prevalence and Incidence

Hypopituitarism is listed as a rare disorder by the National Institutes of Health. To date there are no US-based studies on the prevalence and incidence of hypopituitarism.

One published report indicated it affects less than 200,000 individuals in the US.3 And the 2010 National Hospital Discharge Survey reported 17,101 US inpatient hospital visits with (panhypopituitarism/hypopituitarism) as one of any listed diagnoses, and 749 visits with this as the primary diagnosis. In addition, the reported average hospital stay was 5.4 days.4

Table 1 lists several European-based large-scale studies on prevalence and incidence of hypopituitarism.

 Table 1. Prevalence of all-cause hypopituitarism.
Spain (n=146,000)* Retrospective review of clinical data 45.5 4.21 Regal et al. 20015
Spain (n=405,218) Retrospective review of clinical data 37.5 2.07 Fernandez et al. 20136

Note: *, in this cohort the causes of hypopituitarism were pituitary tumors (61%), non-pituitary lesions (9%), and non-tumor causes (30%, including idiopathic cases [11%]). In addition, approximately 50% of patients had three to five pituitary hormone deficiencies, with luteinizing hormone/follicle stimulating hormone being the most prevalent.

Congenital hypopituitarism is a rare disease, with an estimated incidence of 1:3000 – 1:4000 births.7 Mutations in genes encoding transcription factors and signaling molecules involved in hypothalamo-pituitary development are associated with the different etiologies of congenital hypopituitarism.8-10 Table 2 summarizes the prevalence of the most common mutations among different populations.

 Table 2. Prevalence of genetic mutations associated to congenital hypopituitarism.
POU1F1 The Netherlands; (n=79) 1.2 De Graff et al. 201011
LHX4 Japan;(n=71) 1.4 Dateki et al. 201012
PROP1 International GENHYPOPIT network; (n=195) 13.3 Reynaud et al. 200613

Note: *, in all studies, only patients with multiple pituitary hormone deficiency were studied. All studies included both children and adults.

Acquired hypopituitarism may occur due to a variety of different reasons. Table 3 summarizes the prevalence of some of the most common causes of the disease.

 Table 3. Prevalence of acquired hypopituitarism.
Radiation therapy * PubMed, EMBASE, Web of Science, CINAHL, Academic Search Premier and Cochrane Library Studies on fractionated cranial radiotherapy for nasopharyngeal and intracerebral tumors, adults; (n=813) Systematic review and meta-analysis of studies (1975-2009) 66 Appelman-Dijkstra et al. 201114
Surgery MEDLINE and EMBASE Studies on transsphenoidal surgery for pituitary adenomas; (n=5,643) Systematic review of studies (1990-2011) Endoscopy: 8.51 (5.16-12.59); Microscopy: 11.64 (5.14-20.32) Ammirati et al. 201315
Traumatic brain injury MEDLINE Adults (n=941) and children (n=74) Systematic review of studies (2000-2007) 27.5 Schneider et al. 200716
Aneurysmal subarachnoid hemorrhage MEDLINE Adults (n=122) Systematic review of studies (2000- 2007) 47 Schneider et al. 200716

Note:  *, the risk of acquired hypopituitarism from conventional radiation therapy versus stereotactic radiation therapy has been reported to be similar.17-19

1.1.2 Cost Burden

Although no data exist for US costs, German researchers reported that the annual cost of substitution therapy for patient with hypopituitarism after pituitary surgery in Germany in 2010 was US $1,576 per patient. The costs of lifelong therapy for all patients with new hypopituitarism per year in Germany in 2010 was estimated at US $30.6 million, assuming 45.7% of pituitary surgeries result in hypopituitarism.20

1.1.3 Demographic Differences

Most studies suggest that there are no significant sex differences in the prevalence of this disease (Table 4).

 Table 4. Demographic characteristics of hypopituitarism adult cases.
UK (n=172) 59.3 Median: 53M, 51F N/A 31 69 Bates et al. 199621
Sweden (n=344) 62.2 Mean: 52 (all M/F) Median: 11.9 21.2 78.8 Bulow et al. 199722
UK (n=1,014) 50.69 Median: 46.2 M, 45.3 F Median: 12.1 M, 12.7 F 34.02 65.98 Tomlinson et al. 200123
Sweden (n=1,411) 52.94 Mean: (all M/F) 56.9 N/A N/A N/A Svensson et al. 200424
Netherlands (n=2,229) 52.0 Mean: 43.5 (all M/F) Median: 6.1 N/A N/A Van Bundersen et al. 201125
Global (n=13,983) 51.3 Mean: 43.8 (all M/F Mean: 4.9 N/A N/A Gaillard et al. 201226

Abbreviations: M, male; F, female; n, number; N/A, not available; UK, United Kingdom.

1.4 Life Expectancy and Mortality

Untreated hypopituitarism is associated with serious morbidity and premature mortality.16,27,28 Several studies have shown that adults with hypopituitarism have increased mortality as compared to age- and sex-matched controls, with females having a higher standardized mortality ratio (SMR) than males (Table 5).29,30

 Table 5. Sex differences in all-cause mortality in patients with hypopituitarism.          


2.06 2.8 Nielsen et al. 200730
UK (n=102) 1.5 2.29 Bates et al. 199621
Sweden (n=3,214) 1.91 2.93 Bulow et al. 199722
UK (n=514) 1.57 2.29 Tomlinson et al. 200123
Sweden (n=747) 3.36 4.54 Svensson et al. 200424
Netherlands (n=1,160) 1.06 1.66 Van Bundersen et al. 201125
Global (n=7,174) .94 1.56 Gaillard et al. 201226

Abbreviations: SMR, standardized mortality ratio; UK, United Kingdom.

In Spain, a 10-year follow-up study of 209 hypopituitary patients reported that 32 patients died during the study period, with the SMR being higher in males (8.92 vs. 7.34), and in younger patients (84.83 vs. 5.26). In addition, the diagnosis of acromegaly, previous radiotherapy, higher body mass index, diabetes mellitus, and cancer were associated with enhanced mortality. A lower survival rate was associated with older age at diagnosis, non-tumoral causes, previous radiotherapy, diabetes mellitus with poor metabolic control, and malignant disease.6

Aside from the all-cause mortality being higher in patients with hypopituitarism, specific-cause mortality is also increased in this population. Table 6 lists sex differences in specific-cause SMR.

Table 6. Specific-cause mortality in males and females with acquired hypopituitarism.
Cardiovascular disease Sweden


Retrospective examination (1956-1987) 1.7 2.7 Rosen et al. 199031
Cerebrovascular disease Sweden


Retrospective examination (1952-1992) 2.64 4.91 Bulow et al. 199722
Respiratory disease UK (n=1,014) Patient follow-up (1992-2000) 2.1 3.41 Tomlinson et al. 200123
Note: Studies included patients with different causes of hypopituitarism, including pituitary adenomas and craniopharyngiomas. Patients with acromegaly or Cushing’s disease were excluded from analysis.
Abbreviation: SMR, standardized mortality ratio; UK, United Kingdom.


1.5 Key Trends and Health Outcomes

Hypopituitarism can present itself as either subclinical or clinical, in which case the onset might be acute and severe.32 Due to the diversity of possible pituitary hormone deficiencies that result from this disorder, diagnostic tests for hypopituitarism range from single measurements of baseline hormone levels to dynamic hormone testing. Moreover, since basal concentrations alone might not reflect pulsatile, circadian, or stimulus-specific secretion, dynamic testing may be required to further diagnosis, especially for assessment of adrenal and growth hormone reserve.1,16,32

Hypopituitarism may develop as a result of pituitary tumor treatment. For example, in the case of radiation therapy2, reports indicate that 10 years after conventional fractionated irradiation, 50% of patients exhibit varying degrees of hypopituitarism.33,34 Similarly, Gamma Knife surgery resection has been associated with an increased risk of developing hypopituitarism.35

In addition, hypopituitarism may develop after pituitary surgery, depending on factors such as tumor size, degree of infiltration, and surgeon experience.2 For example, one study reported that 0, 7.2, and 13.6% of patients with tumor diameters of <20, 20-29, and ≥30 mm, respectively, developed new hypopituitarism after endonasal transsphenoidal adenoma removal.36 Resolution of the disorder has been related to younger age (39 vs. 52 years), and absence of intraoperative cerebrospinal fluid leak.36 Additional factors associated with a higher recovery of post-operative pituitary function include no tumor rests on post-operative pituitary imaging, and no pathological evidence of an invasive nature.37

In terms of the specific types of post-operative hormone deficiencies, Webb and colleagues reported that in 234 patients with pituitary adenomas, 52 patients developed new post-operative pituitary hypofunction: 27% ACTH deficiency, 14.5% growth hormone (GH) deficiency, 10.5% thyroid-stimulating hormone deficiency, 16.5% gonadotropin deficiency, and 13% prolactin deficiency.37 Importantly, approximately 50% of patients recover at least one of the pituitary hormone deficiencies caused by surgery during the immediate post-operative stage.37,38

In the particular case of GH deficiency, it has been shown that adults with primary hypothalamic-pituitary diseases before and after any medical intervention (defined as neurosurgery, radiotherapy and medical therapy) are at greater than 80% risk of severe GH deficiency.39 Moreover, a study in Denmark reported that GH deficiency increased mortality in both genders, when compared with controls.40 The Endocrine Society 2011 Clinical Practice Guideline for the Evaluation and Treatment of Adult Growth Hormone Deficiency provides detailed recommendations for the diagnosis and management of this type of pituitary deficiency.2

Overall, adequate hormone replacement can improve quality of life, morbidity, and mortality associated with hypopituitarism.32 Table 7 summarizes health outcomes data for adrenocorticotropic and GH deficiencies.

 Table 7. Effects of hormone substitution therapies on hypopituitarism
ACTH Once-daily oral hydrocortisone dual-release tablet * Germany; multicenter clinical trial and university hospital centers (n=64) Sustained serum cortisol profile, reduced weight, blood pressure and improved glucose metabolism versus 3 times/day conventional hydrocortisone tablets. Johannson et al. 201241


GH therapy


Endocrine Society Clinical Practice Guideline. Review of studies Benefits in body composition, bone health, cardiovascular risk, and quality of life. Molitch et al. 20112
11 countries; The Hypopituitary Control and Complications Study, 2000, adult onset (n=1,123) After 3 years on GH-therapy, serum cholesterol and body fat percentage decreased in females (-0.31 ± 1.04 mmol/liter; -3.07 ± 7.77) and males (-0.40 ± 1.04 mmol/liter; -2.84 ± 6.76) Attanasio et al. 200242
Sweden; retrospective analysis of adults without GH therapy, 1987-1992 (n=1,411) versus prospective study of GH-treated patients, 1990-2000 (n=289) Overall mortality: without GH (RR, 3.8) > GH-treated (RR, 0.84)

All malignancies: without GH (RR, 1.83) > GH-treated (RR, 0.88)

Svensson et al. 200424
Abbreviations: ACTH, adrenocorticotropic hormone; GH, growth hormone; RR, risk ratio.

Note: *, this preparation is not available in the US. In the US, hydrocortisone is generally given in 2 or 3 doses over the course of the day; the usual total daily dose is 15-20 mg/day and rarely exceeds 30 mg/day.

Importantly, hypopituitarism may present a number of comorbidities including, dyslipidemia, cardiovascular complications, and osteoporosis. Thus, treating hypopituitarism, in addition to pituitary hormone substitution, may include managing comorbidities.32


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