rel="nofollow" href="#ulink_445f76f3-4f56-51be-8eff-a4d9102ed7be">13]. Important interactions with thyroxin, GH, and sex steroids should not be ignored since they can induce cortisol clearance and increase the risk for adrenal crisis [20].
The aim of daily GC replacement is to deliver sufficient cortisol for day to day activity in unstressed condition. However increased doses are needed during stressful conditions (surgery, trauma, acute illness). The aim of chronic GC replacement is to avoid under- and over-replacement in order to avoid adverse cardiometabolic risk and increased mortality as stated in the current guidelines and recommendations [87, 93].
Thyroxin and Metabolic Phenotype
Untreated mild or poorly replaced central hypothyroidism (CH) may potentially contribute to adverse cardiometabolic risk. In CH bioactivity of TSH is reduced due to abnormal glycosilation, TSH half-life is longer and thyroid hormones may be within the lower normal range [94]. Patients with untreated GHD may have higher T4 levels since GH replacement increases and GC reduces T4–T3 conversion [93–95]. Estrogen treatment increases thyroid binding globulin and patients may need higher doses of T4 replacement. Recommendations for adequate T4 replacement in CH are based on few reports that suggest direct dosing by weight using mean dose of 1.6 µg/kg targeting TSH below 0.1 mU/L and FT4 in mid to high normal reference range [87]. Patients with CH on empirical T4 doses 1 µg/kg had worse outcome in terms of BMI, total, LDL, and HDL cholesterol than patients on doses 1.6 µg/kg [22].
Sex Steroids and Metabolic Phenotype
Because estrogen antagonizes the metabolic actions of GH on the liver it should be replaced by a non-oral route in women with hypopituitarism [25]. For hypopituitary women with GHD, estrogen replacement will worsen GHD state and for those taking oral estrogen during GHRT, it will reduce therapeutic benefit of GH [23–25]. In a single survey, only 19% of GHD women received estrogens via transdermal route [23]. On the other hand, oral estrogen replacement substantially increased the dose (55–70%) and cost of GHRT compared to transdermal patches (20–30%) [25]. When contraceptives are prescribed instead of replacement doses the waste is even greater [96].
Testosterone and GH exert similar effects on body composition and physical function. They also act together in augmenting each other’s effects. In men with hypopituitarism, concomitant GH and testosterone replacement are needed to achieve optimal effects. The adverse effects are however more frequent when co-administered and for this reason stepwise introduction of GH and testosterone replacement with gradual dose adjustment is advised [25].
Newer Data on Metabolic and Cardiovascular Outcome in Patients with Hypopituitarism on Long-Term GHRT
In the last years abundance of new data became available regarding metabolic and cardiovascular outcomes in patients with hypopituitarism. Meta analysis of 6 studies up to 2014 reporting a total of 19,153 patients confirmed 2-fold increased overall mortality for hypopituitarism, especially in female and patients diagnosed at younger age [97]. GHRT improved mortality risk in hypopituitary adults that was comparable to the background population, but this benefit was lower for women than man [97]. These data are similar to the latest Swedish nationwide study reporting increased SMRs for patients diagnosed with NFPA (the most common cause of adult hypopituitarism) at age younger than 40 years and women with hypopituitarism and diabetes insipidus [98]. SMRs were also increased for cerebrovascular and infectious diseases and decreased for malignant tumors in hypopituitary patients with NFPA etiology [98]. These trends of increased mortality in female patients appear to be declining, at least for women diagnosed during the last decade (after 2007), possibly due to decreasing prevalence of pituitary insufficiency and better replacement [99]. Another analysis, of life expectancy in hypopituitary patients with NFPA, confirmed that patients receiving long-term GHRT had reduced overall mortality compared to the general population [100]. Death from malignancy was not increased and long-term GHRT appeared to be safe in adult patients selected for treatment [100]. Similar findings were reported from HypoCCS database [101]. There was no increased risk for all-site cancers, breast, prostate, or colorectal cancers in GH-treated patients [101]. Furthermore, GHRT did not increase the risk of pituitary adenoma or craniopharyngeoma recurrences [101]. Another systematic review and meta-analysis, which included 15 studies published from 1995 to 2015 and total of 46,148 patients, supported the overall safety of GHRT in adults with hypopituitarism with no clear evidence of increased risk of pituitary tumor recurrence, malignancy, or stroke [97]. Hypertension and age >55 years were found to be major prognosticators of adverse cardiovascular outcome in non-diabetic patients with GHD during the long-term follow-up (12 years) suggesting the need for optimal control of all cardiovascular risk factors especially hypertension in these patients [102]. The most recent data showed reduced all-cause mortality (and death from malignancy) in hypopituitary patients with NFPA treated with GHRT suggesting that long-term GHRT is safe in these patients [103].
Conclusion
We should realize the cumulative effect of dysfunction of multiple pituitary hormonal axes on adverse metabolic and cardiovascular disease profile. We should also understand the challenges in pituitary replacement therapy and interaction between hormones used for replacement in hypopituitarism (e.g. excessive HC coupled with suboptimal treatment of other pituitary hormone deficiencies) and how this may contribute to the adverse cardiometabolic milieu. Pro-active treatment of all associated cardiometabolic comorbidities and risk factors is also advocated as well as the regular risk assessment and re-evaluation during the long-term follow-up.
References
1Pekic S, Popovic V: Expanding the cause of hypopituitarism. Eur J Endocrinol 2017;176:R269–R282.
2Van
