LAUSR

I read with interest the review paper “Vaginal progesterone and the vaginal first-pass effect” by M. P. Warren, published in your Journal. This is an interesting work; however, I have concerns about some misleading information contained in the review. The author writes, as her first sentence, that ‘Delivery of progesterone to the vagina is a form of transdermal delivery... .’ However, the vagina is a mucosa, not really a skin ... so transdermal delivery is ‘misleading’. Therefore, delivery of progesterone to the vagina is a form of systemic delivery. Subsequently, the author affirms that ‘... This direct vaginato-uterus transport produces endometrial changes similar to those seen in the luteal phase, despite plasma progesterone levels that remain subphysiologic.’ This is untrue. Plasma levels can be ‘physiologic’ (reaching about 10–15 ng/dl depending on the daily dose, which is an adequate level at the midluteal phase in natural cycles), as shown with micronized progesterone capsules used for luteal phase support in assisted reproductive technology (at the dose of 600mg/ day). Further: ‘... This method circumvents or attenuates the progesterone-negating benefits on the cardiovascular system... .’ This is true for medroxyprogesterone acetate, a synthetic progestogen, but untrue for micronized progesterone on cardiovascular surrogate risk markers. In reporting the anesthetic activities of natural micronized progesterone, the author refers to the report of Ararat and colleagues, where the authors identified significant quantities of metabolic end-products that have been shown to possess anesthetic qualities. But this is again untrue, since it is only in the case of very high doses in animals, but never in human clinical practice at the prescribed usual doses up to 400mg/day (approved by FDA Prometrium PI Product Information). The author also affirms that ‘progesterone is not well absorbed through the skin... .’ This statement is again untrue. Transdermal progesterone (e.g. ProgestogelR gel) penetrates through the skin, increasing significantly the levels in breast tissue, saliva and capillaries. I would like also to point out that the galenic form, sonamed ‘suppository’, is designed for rectal administration, not for vaginal. Therefore, the terminology vaginal ‘pessary’ or ‘soft capsules’ is more appropriate. Finally, the author affirms that ‘Recently, a progesterone gel formulation (Crinone) has been designed for vaginal use... .’ However, Crinone was approved by the FDA in 1997. I appreciate the efforts carried out by the author to write an up-to-date review of this important topic, but I suggest these points should be checked in order not to disseminate wrong information to readers.