Valproate, antipsychotic drugs and HAART have additional endocrine disruptor effects
PCOS, NCAH, glucose intolerance, lipodystrophy and dyslipidemia may develop with these various treatments.
It is now well-known that the above drugs are associated with the development of metabolic syndrome. Particularly well-documented are the increased risk of developing polycystic ovarian syndrome (PCOS) while taking valproate, the tendency to develop glucose intolerance while on atypical antipsychotics, and the tendency to develop lipodystrophy and dyslipidemia while taking protease inhibitors and nucleoside analogues.
It is well-established that women with PCOS are usually insulin resistant and improve clinically and biochemically with weight loss, diazoxide, metformin, and PPAR-gamma agonists, all of which decrease circulating insulin levels.
In addition, Seto-Young et al have recently demonstrated that thiazolidinediones (TZDs), as PPAR-gamma agonists, may exert direct effects upon ovarian steroidogenesis distinct from local and systemic enhancement of insulin sensitivity.
Speiser et al have shown that women with nonclassical 21-hydroxylase deficiency are insulin resistant. We have shown that interventions that increase insulin sensitivity (weight loss, exercise, metformin and TZDs) all improve all known types of nonclassical adrenal hyperplasia (NCAH) both clinically and biochemically, just as they do in PCOS.
Drug-induced endocrine disruption
One common denominator for both PCOS and NCAH — besides their indistinguishable clinical presentations, their frequent coexistence in the same patient and their frequent cross-suppressibility — is that hyperinsulinemia causes a post-translational change in P450c17 alpha. Patients with PCOS frequently suppress their elevated serum androgens with glucocorticoids while those with NCAH often suppress their elevated androgen levels with oral contraceptives.
Hyperinsulinemia causes P450c17 alpha to become hyperphosphorylated, leading to a gain in function in this enzyme that catalyzes a rate-limiting step in both ovarian and adrenal androgen biosynthesis.
The increased activity of P450c17 alpha, described by Arslanian and colleagues, will magnify any downstream enzyme hypofunction, which may have been biochemically and clinically silent in the absence of hyperinsulinemia.
We extended the concept of drug-induced endocrine disruption to include not only the known effects of their induction of insulin resistance on carbohydrate and lipid metabolism and body fat distribution, but also upon adrenal steroidogenesis. To do this, we studied 31 consecutive men and women patients (aged 19 to 79 years) taking valproate and/or a classical or atypical antipsychotic agent.
Two drug classes
All patients had NCAH. Patients presented with findings such as hirsutism, acne, alopecia, menstrual abnormalities, acne, acanthosis nigricans and central obesity. Eight out of eight patients normalized their abnormal steroid metabolites and SHBG levels on metformin, while two out of two patients normalized their elevated steroid metabolites on rosiglitazone.
We next focused on two other drug classes known to cause insulin resistance: the protease inhibitors and the nucleoside analogues, components of highly active antiretroviral therapy (HAART).
We studied four women and five men aged 28 to 69. All patients had NCAH. We have not yet treated these patients with insulin sensitizers (see table 1).
Thus, we have described an additional dimension of endocrine disruption due to five classes of commonly prescribed drugs. Presumably, the induction of NCAH by these drugs is largely an aspect of their insulin-desensitizing effects. This hypothesis by no means obviates other contributions to the dysregulation of adrenal steroidogenesis in patients on HAART.
For example, the classical and atypical antipsychotic drugs all increase prolactin secretion, which, in turn, increases both ovarian and adrenal androgen production.
That prolactin may not always be a crucial factor in adrenal steroidogenesis is shown in a patient we are currently following whose elevated 17-OH-progesterone level promptly fell to normal on metformin 500 mg/day while her prolactin level remains quite elevated. Macroprolactinemia has been ruled out.
Patients with HIV infection and several of its associated opportunistic infections frequently have adrenal insufficiency — which may be partial — affecting certain steroidogenic enzymes more than others. This results in an acquired form of adrenal hyperplasia, which could be exacerbated by the addition of insulin resistance resulting in increased upstream activity of P450c17 alpha.
Recently, Ambrosi and associates have shown that about 50% of patients with Cushing’s syndrome of central origin normalize their urinary cortisol excretion when given rosiglitazone.
PPAR-gamma may regulate adrenal steroidogenesis at several levels. First, it is known that rosiglitazone suppresses ACTH secretion in mice and in the AtT20 pituitary tumor cell line. In Ambrosi’s study it reduced ACTH levels, though not significantly, in six Cushing’s disease patients in whom urinary free cortisol excretion was significantly reduced.
This could be due to both systemic insulin sensitizing effects or local effects on corticotroph cells expressing PPAR-gamma involving both insulin-sensitizing and insulin-independent effects.
Effect of TZDs
There is also likely to be a direct effect of PPAR-gamma upon the adrenal cortex, analogous to what Seto-Young et al have reported in ovarian cultures. TZDs suppress androgen synthesis in the presence of added insulin and to some extent even in the absence of added insulin, suggesting local as well as systemic insulin-sensitizing effects of these compounds as well as PPAR-gamma effects distinct from insulin sensitization. For example, TZDs have recently been reported to directly suppress the activity of both P450c17 alpha and 3-beta-ol-dehydrogenase.
Recently it has been reported that dopaminergic blockade, particularly of the D2 receptor, can itself contribute to insulin resistance. Since these antipsychotic drugs all block this receptor to some extent, this provides an alternative mechanism by which insulin resistance, and as a consequence adrenal/ovarian hyperandrogenism, may occur in patients taking these drugs.
For more information:
- Alan Sacerdote, MD, is an Associate Professor of Medicine at SUNY Downstate Medical Center in Brooklyn, New York. He is a member of Endocrine Today’s Editorial Board.
- Speiser PW, Serrat J, New MI, Gertner M. Insulin insensitivity in adrenal hyperplasia due to non-classical steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1992;75:1421-1424.
- Arslanian SA, Lewy V, Damadian K, Saad R. Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance. J Clin Endocrinol Metab. 2002;87:1555-1559.
- Ambrosi B, Dall’Asta C, Cannavo S, Libe R, et al. Effects of chronic administration of PPAR-gamma ligand rosiglitazone in Cushing’s disease. Eur J Endocrinol. 2004 Aug;151:173-8.
- Seto-Young D, Paliou M, Schlosser J, Avtanski D, et al. Direct thiazolidinedione action in the human ovary: Insulin-independent and insulin-sensitizing effects on steroidogenesis and insulin-like growth factor. J Clin Endocrinol Metab. 2005;90:6099-6105.
- Pijl H. Reduced dopaminergic tone in hypothalamic neural circuits: expression of a “thrifty” genotype underlying the metabolic syndrome? Eur J Pharmacol. 2003;480:125-31.