followed by gonadotropins (luteinizing hormone and follicle stimulating hormones), thyreotropin or thyroid stimulating hormone (TSH), and corticotropin (ACTH). Vast majority of patients with hypopituitarism have multiple pituitary hormone deficiencies (MPHDs) usually with more than 2 or 3 axes affected. Hypopituitarism is a dynamic variable throughout follow-up. It may be permanent and progressive with sequential pattern of hormone deficiencies or transient with possible recovery occurring years from the initial event. Longitudinal follow-up, retesting, and adequate replacement are essential.
The Metabolic Syndrome
The current criteria define metabolic syndrome (MetS) as a cluster of cardiometabolic risk factors: obesity, large waist circumference (visceral obesity), impaired glucose metabolism with insulin resistance, dyslipidemia, and arterial hypertension. These are commonly associated with obesity, type 2 diabetes mellitus, and cardiovascular diseases in the general population. Interestingly, the prevalence of MetS is also significantly increased in patients with hypopituitarism compared to the general population by 20–50% [2–8].
In several studies investigating prevalence of MetS in patients with hypopituitarism, MetS was scored using NCEP-ATP III criteria published in 2001 [9]. These criteria define MetS as the presence of 3 or more of the following: fasting plasma glucose >6.1 mmol/L, triglycerides >1.69 mmol/L, HDL <1.04 mmol/L in men and <1.29 mmol/L in women, blood pressure (BP) >130/85 mm Hg, waist circumference >102 in men and >88 cm in women, and body mass index (BMI) >30 [9].
Clinical Relevance of Metabolic Phenotype in Hypopituitarism
Hypopituitarism removes the natural survival advantage that women have over men. Highest mortality is among younger patients, women, and patients with diabetes insipidus [10–12]. Most common causes of death in patients with hypopituitarism are cardiovascular and cerebrovascular designated to the associated MetS and treatment modalities such as cranial irradiation. Conventional sequential radiotherapy was reported to be associated with post irradiation vasculopathy and an increased risk of cerebrovascular complications in previous studies [10, 14]. Weather the cranial irradiation affects central regulation of metabolism, which could in theory independently of hypopituitarism affect the metabolic profile of these patients, is currently unexplored. Transcranial surgery, etiology (caniopharyngeoma, aggressive pituitary adenoma), and presence of diabetes insipidus are also associated with more extensive, aggressive disease and increased mortality [10–13].
After the first data on excess mortality from cardio-vascular causes in adult patients with hypopituitarism, receiving conventional replacement without GH therapy, clinical efforts were made to define and replace GH deficiency (GHD) in adults as the major cause of MetS phenotype and increased vascular risk in these patients. Studies that followed, reported cardio-vascular mortality rates, for patients with GHD treated with GH, that were similar to the background population suggesting amelioration with GH replacement [14]. GH replacement appeared to provide protection from myocardial infarction [14]. Data on cerebrovascular events during 5 years of GH replacement showed persistence of increased mortality rates [14]. Adult patients with craniopharyngeoma (more obese with more severe MetS and pituitary deficiencies, including diabetes insipidus) seemed to respond equally well to GH treatment as patients with non-functioning pituitary adenoma (NFPA), but were less likely to lose body fat [15]. Despite improvement in lipid profiles and body composition parameters during GH replacement, several studies reported no change in the prevalence of MetS after 2–5 years of treatment [2, 4, 16]. An increase in the prevalence of MetS after 10 years of low-dose GH replacement due to steady increase in BMI, waist circumference, and BP, despite improvement in lipid profile, was reported recently [7]. The increase in the MetS prevalence was higher than expected with aging alone [7]. Furthermore, data regarding the prevalence of diabetes mellitus in GH treated versus untreated patients with adult-onset of hypopituitarism are still lacking. Results of safety surveillance studies from large databases during the long term follow-up are controversial reporting improvement, neutral or even unfavorable effects on glucose metabolism and tolerance with increased incidence of diabetes in female patients and hypopituitary patients with MetS [5, 6, 16].
Up to now, few studies have focused on the impact of other replacement therapies with glucocorticoids (GC), thyroxin (T4), and sex steroids on features of the MetS and mortality rates in patients with hypopituitarism [17–19]. It has been suggested that some hormone replacement regimes, such as overzealous replacement with hydrocortisone (HC), T4 under-replacement, unreplaced hypogonadism, or the use of oral contraceptives for replacement of female patients during GH therapy, may also contribute to adverse outcomes and MetS phenotype in patients with hypopituitarism [16–25].
Prevalence of MetS in Patients with Hypopituitarism
In 50 Dutch hypopituitary patients with adult-onset GHD, prevalence of MetS was increased by more than 2-fold compared with the general population (38 vs. 15.7%). Hypertriglyceridemia (46 vs. 18%), hypertension (66 vs. 35.5%), and abdominal obesity (38 vs. 23.4%) were significantly more prevalent in patients with hypopituitarism than that in the general population [2]. Prevalence of MetS did not change after 2 and 5 years of treatment with GH [2].
Study of adult hypopituitary GHD patients from Hypopituitary Control and Complications Study (HypoCCS) data base (n = 2,531) reported prevalence of MetS in 42.3% (51.8% in USA and 28.6% in Europe) of patients [4]. The difference in MetS prevalence between USA and Europe was due to obesity prevalence (75% of USA patients were overweight or obese) and lower proportion of younger patients with childhood onset disease [4]. Increased MetS risk was observed for age >40 years, female sex, and adult onset of the disease [4]. In GH treated patients MetS prevalence was not changed after 3 years [4].
KIMS (Pfizer International Metabolic Database) database