What is the difference between graves’ disease and cushing disease

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Keil, C. Lyssikatos, E. Belyavskaya, C. Stratakis, and M. Bernad, C. Furthermore, the higher prevalence of central hypothyroidism in ACTH-secreting microadenomas compared with microprolactinomas and non-functioning microadenomas has been reported [ 25 ], confirming the role of hypercortisolism in the genesis of central hypothyroidism.

Endogenous hypercortisolism also reduces thyroid hormone action on peripheral tissues by other mechanisms. The decreased T3:T4 often reported can be due to GC-mediated inhibition of peripheral deiodination [ 26 ]. Consistent with this, after curative surgery, T3 levels increased disproportionately to T4 and FT4, reflecting the possible recovery of the type 1 and type 2 deiodinase activity, which converts T4 to T3, after the resolution of hypercortisolism [ 27 ].

Moreover, hypercortisolism is associated to a reduction in thyroxin biding globulin TBG [ 24 ], which contributes to the reduced T3 and T4 concentration. The effects of hypercortisolism on the HPT axis are summarized in Figure 1. The influence of hypercortisolism on the hypothalamus—pituitary—thyroid HPT axis regulation: thyrotropin-releasing hormone TRH derived from the parvocellular neurons of the hypothalamic paraventricular nucleus PVN , stimulates TSH synthesis and secretion from thyrotroph cells located in the anterior pituitary gland.

In turn, TSH regulates thyroid hormone production and release via binding to the TSH receptor in thyroid follicular cells. At the pituitary level, hypercortisolism directly inhibits TSH secretion. Hypercortisolism also inhibits the peripheral deiodination of thyroid hormones with a consequent decrease in T3:T4 ratio. The dynamic changes of thyroid function and the recovery time of HPT axis normal activity have been evaluated by different clinical studies.

A prospective study performed on 27 patients with pituitary 16 patients and adrenal 11 patients CS showed reduced TSH secretion and TSH pulse mass during active disease, independently of hypercortisolism etiology [ 28 ].

Interestingly, FT4 levels were decreased only in pituitary-dependent hypercortisolism compared with controls. However, in this study, the cortisol production rate was higher in patients with CD than in patients with an adrenal adenoma, and total cortisol production was negatively correlated with TSH production and with FT4 concentration.

Therefore, the more severe degree of hypercortisolism in CD in this specific group of patients could explain the specific correlation between CD and hypothyroxinemia. The reduction of TSH levels during the active disease has been confirmed by other prospective studies, involving similar groups of patients [ 29 , 30 ], as well as the return to normal thyroid function after the cure of hypercortisolism [ 30 ].

On the contrary, other authors showed similar serum FT3 and FT4 levels in CS patients and controls, both during the active disease phase and after successful treatment [ 30 ]. Xiang and et al. TSH, T3, and FT3 were negatively correlated with serum cortisol levels, both before and after surgery, while no significant changes in anti-thyroid autoantibodies were observed [ 31 ]. A recent study retrospectively evaluated the thyroid function in two groups of patients affected by CS cohort 1, 68 patients and cohort 2, 55 patients, who performed follow-up in different years , before and after successful surgery [ 27 ].

The alteration in thyroid function was reversible after the remission of hypercortisolism mean time of recovery: 8 months , and the degree of central hypothyroidism was related to the duration of symptoms, morning and midnight serum cortisol, and urinary-free cortisol [ 27 ]. In addition, secondary hypogonadism was more frequent in CS patients affected by hypothyroidism [ 27 ].

This can be explained by an additional effect of hypercortisolemia on other hypothalamic—pituitary axes and by the fact that a normal hypothalamic—pituitary—gonadal axis function requires an intact HPT axis [ 27 , 32 ].

Cai et al. Reduced TSH levels during the active phase of the disease have been confirmed, but in contrast with previous studies, FT4 levels were lower also in ACTH-independent hypercortisolism when compared with controls.

On the contrary, data about the reduction of FT3 and FT4 levels are conflicting, which is probably due to the presence of heterogeneous groups of patients as well as to the different nature of the studies retrospective vs. Overall, the changes in thyroid function seem to be reversed with successful treatment with a recovery time that is inversely related to the severity of hypercortisolism.

A retrospective evaluation of 59 patients with CS found that Moreover, the resolution of hypercortisolism seems to represent a trigger for the development of autoimmune disorders. In humans, the most frequently reported autoimmune diseases after the remission of CS are autoimmune thyroid diseases [ 35 ].

The first observations have been reported by Takasu et al. In those years, great interest developed about the immunoendocrine interactions and autoimmunity.

It is reasonable to hypothesize that in patients with underlying autoimmune thyroid disease, the inappropriate cortisol secretion guarantees an immunologic tolerance masking the overt thyroid dysfunction, which develops only after the remission of hypercortisolism. It is well known that glucocorticoid excess exerts an inhibitory action on immune function in humans, as confirmed by the involution of lymphoid tissue and by the increased susceptibility to infections detected in patients with CS [ 35 , 38 ].

In his Editorial, McGregor commented on the three cases of CS previously described by Takasu, who developed after adrenalectomy a first phase of transient hyperthyroidism with the characteristics of a destructive thyroiditis, followed by hypothyroidism, and compared the immunological bases of this condition with that of post-partum thyroiditis [ 38 ]. Colao and coll. Furthermore, the development of autoimmune thyroiditis during the remission was significantly associated with the presence of a previous nodular goiter or positive thyroid autoantibodies titer during the active phase of the disease [ 30 ].

Other studies and case reports confirmed the increase in anti-thyroid antibodies titer after the resolution of hypercortisolism [ 42 ]. In the retrospective analysis of Niepomniszcze and coll. In line with this, animal models employed to elucidate the impact of basal levels of adrenal gland-derived glucocorticoids on T cell activity showed that the withdrawal of adrenal glucocorticoids produces alterations in the thymocyte selection processes, increasing the risk to generate potentially self-reactive cells [ 48 ].

The first patient developed DQT symptoms fever, neck pain, thyrotoxicosis during medical treatment with pasireotide, while the second patient had the same symptoms after monolateral adrenalectomy for ACTH-independent CS. As reported by the authors, DQT, which is a steroids-responsive condition, occurred in both patients after the reduction of endogenous serum cortisol [ 51 ]. Another hypothesis is that the reduction of serum cortisol could affect the thyroid cells by inducing damage on vascular smooth muscle cells and on the endothelium [ 51 ].

After the exclusion of possible laboratory interferences, TSH-secreting pituitary adenoma TSHoma or resistance to thyroid hormones syndrome should be suspected. In , Tamada et al. Other causes of SITS were excluded. The authors also checked thyroid function in another seven patients who underwent successful surgery for CS and reported five cases of inappropriate TSH secretion, developing within 2 months after surgery [ 53 ]. The increase of thyroid hormones levels and the inability to adequate suppress TSH detected in SITS patients can be due to an impaired deiodinase activity.

Type 2 deiodinase converts T4 to T3 in several tissues, including the hypothalamus and pituitary and contributes to the regulation of the HPT axis, regulating the local concentration of T3 [ 8 ]. Tamada et al. In the prospective study by Dogansen et al. The authors explained that these findings could be due to the adequate post-operative replacement treatment with prednisolone in their cohort [ 24 ].

Medical therapies are used to control hypercortisolism before surgery or as a second-line option in patients in whom surgery is not curative or not possible, especially in ACTH-dependent CS. Three main drug categories are usually employed: pituitary-directed drugs, including pasireotide and cabergoline, aimed to reduce the ACTH production; steroidogenesis inhibitors, including ketoconazole, metyrapone, and mitotane; and glucocorticoid receptor GR antagonist, mainly represented by mifepristone.

Pituitary directed medical therapies are aimed to target the underlying cause of the disease, to reduce the ACTH secretion and inhibit tumor growth. Although pasireotide and cabergoline can be used for the biochemical control of the inappropriate TSH secretion in TSHomas [ 56 , 57 ], data regarding their effects on HPT axis activity in patients with CS are lacking and not well elucidated.

Pasireotide is currently the only pituitary-directed drug with an official license by the European Medical Agency EMA and the American Food and Drug Administration FDA for the treatment of CD in patients for whom surgery is not an option or in case of persistent disease after surgery [ 60 ].

However, studies evaluating the effects of pasireotide on the hypothalamus—pituitary—thyroid axis are lacking. In primary cultures of rat pituicytes, pasireotide dose-dependently inhibited GH and TSH release, while in cultures of human fetal pituitary cells, pasireotide inhibited GH secretion but had no effect on TSH release [ 61 ].

In an above-mentioned case report [ 51 ], the use of pasireotide has been associated with the development of DQT, but more as the consequence of the reduction in serum cortisol levels rather than a direct drug-mediated effect. To our knowledge, no drug-related effects on HPT axis have been reported in CD patients treated with cabergoline. In a small group of women with hyperprolactinemia treated with cabergoline, no variation in basal and TRH-stimulated TSH levels was found during medical treatment [ 62 ].

The steroidogenesis inhibitors are adrenal-directed drugs that induce a decrease in cortisol secretion through the inhibition of specific enzyme pathways [ 60 ]. The drugs available to date include metyrapone, ketoconazole, and mitotane. Furthermore, this drug also acts on ACTH secretion, suggesting a possible double effect in the treatment of CD patients [ 60 ]. Science News.

ScienceDaily, 23 June Michigan State University. Cushing disease: Often a victim of mistaken identity. Retrieved November 10, from www. A new study indicates that it is the location of the fat that matters most, with abdominal fat representing the greatest Before surgery, there was no difference in mean TSH between daytime and nighttime. A mean 8 months after surgery, the second group had a normal nocturnal TSH surge from 1. The nocturnal TSH increase persisted as long as 3 years in participants who had follow-up evaluations.

We also noted a strong correlation between hypothyroidism and hypogonadism, which implies that hypothyroid patients are also likely to suffer adverse reproductive effects. Even after thyroid function is restored, regular follow-up should also be conducted. Skand Shekhar, MD, can be reached at skand.

Patients with ACTH-secreting adenomas, even smaller ones, have been found to have a higher than expected prevalence of central hypothyroidism compared with other patients with pituitary adenomas of the same size.

This is presumed to be due to glucocorticoid-induced suppression of the hypothalamic-pituitary-thyroid axis. Excess cortisol can decrease thyroid hormone action at multiple levels, including hypothalamus, pituitary, liver and other peripheral tissues. An interesting finding was that untreated central hypothyroidism was higher than previously thought, in approximately half of patients. The authors also observed normalization of nocturnal TSH secretion, T 3 and T 4 levels after treatment.

Furthermore, preoperative cortisol exposure has been correlated with diminished thyroid hormone both before and after the surgery; thus, we can predict which patients are at higher risk for developing thyroid dysfunction. I agree with the authors that a wait-and-watch approach in patients with mild central hypothyroidism without clinical symptoms can be taken after curative surgery, as most will recover over time.