Peter Kovacs, MD, PhD

Disclosures

June 24, 2004

Question

Is there any merit in treating elevated dehydroepiandrosterone (DHEAS) levels in thin women with polycystic ovary syndrome (PCOS) with metformin to improve chances of fertility and prevent recurrent miscarriages? Should such women also be given steroids?

P. Vaidyanathan, FRCSC, FRCOG, FACOG

Response from Peter Kovacs, MD, PhD

PCOS is characterized by menstrual irregularities and hyperandrogenism. Androgens (testosterone, androstenedione, DHEA, and DHEA sulfate [DHEAS]) are produced by the ovaries and the adrenal glands. In addition, androgens are derived from the peripheral conversion of estrogens. A fraction of the total androgens consists of androgen bound to proteins in the circulation; it is the free, unbound fraction that is responsible for the clinical effects. The adrenal gland produces about 25% of the circulating testosterone, 50% of androstenedione, and 90% of DHEAS. Most patients with PCOS will have increased testosterone levels, but 25% to 50% of them will also have elevated DHEAS.

The exact etiology of adrenal androgen excess is not known. Increased adrenocorticotropic hormone (ACTH) production, increased adrenal sensitivity to ACTH, altered steroidogenic enzyme activity (17-20 lyase, 3-beta-hydroxysteroid dehydrogenase activity), and an overproduction of androgens in response to hyperprolactinemia have all been implicated as potential mechanisms. Others have suggested a role for abnormal glucose metabolism (hyperinsulinemia; insulin resistance is a characteristic feature of PCOS) in the adrenal androgen excess.

A connection between ovarian estrogen production and adrenal androgen synthesis has also been evaluated. Estrogens could have a direct adrenal effect or their effect could be mediated via prolactin. Estrogens are known to increase pituitary prolactin secretion, which in turn will augment adrenal DHEAS output. The induction of hypoestrogenism with gonadotropin-releasing hormone agonist reduces DHEAS levels. Some of these metabolic characteristics may have a genetic background.

These potential pathways leave us with numerous possibilities for medical intervention. Before choosing the treatment, we need to decide what symptom we are planning to manage (eg, infertility, recurrent miscarriage, hirsutism, acne, or menstrual irregularity). If our goal is to restore ovulatory cycles, then selective estrogen receptor modulators (eg, clomiphene citrate [CC]), insulin-sensitizing agents (eg, metformin), gonadotropins, bromocriptine (in the case of hyperprolactinemia), glucocorticoids, aromatase inhibitors, or ovarian drilling could all be offered. Most of these drugs have been shown to be effective in restoring menstrual cyclicity, although their efficacy varies. In addition, they are associated with different risk-benefit profiles. The agent with the least side effects and best safety profile should be chosen first. Because hyperinsulinemia has been suggested as a possible mechanism leading to increased adrenal DHEAS production, the use of metformin is likely to lower DHEAS levels as well. However, it is my opinion that metformin should not be administered with the sole indication to lower high DHEAS levels; treatment should address the patient's complaint. During metformin administration, androgen levels will be reduced, and in over 50% of the patients, ovarian cyclic function will be restored. Metformin administered in early pregnancy will lower miscarriage rates as well.

Glucocorticoids (eg, dexamethasone 0.5-2.0 mg) have been shown to improve menstrual regularity in up to 60% of women with PCOS. However, success rates significantly vary from study to study. The combination of CC and dexamethasone also has been shown to be effective for CC-resistant women with PCOS. At this point, it is unclear which patient might benefit from additional dexamethasone therapy. Biochemical parameters (various baseline androgen levels) were mostly shown not to be predictive of response. It is also unclear which dose of dexamethasone leads to the best results, and for how long it should be administered. Long-term steroid administration is associated with significant side effects (eg, weight gain, osteoporosis, gastrointestinal problems, and glucose intolerance); therefore, its use should be limited. As there are numerous, safer treatment options that are available to manage the various problems that arise among women with PCOS, the use of glucocorticoids should be reserved for those who fail other interventions.

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