The primary and non-negotiable Progestin's Role in combination Hormone Replacement Therapy (EPT) is to counteract the proliferative effect of estrogen on the endometrium, thereby preventing endometrial hyperplasia and reducing the risk of uterine cancer in women with an intact uterus. This protective function is essential for safe long-term use. Progestins are delivered either sequentially (to induce a periodic withdrawal bleed) or continuously (to maintain amenorrhea).

Beyond this primary function, the specific progestogen chosen can exert heterogeneous effects on other systems due to its affinity for various steroid receptors. Different progestins (e.g., micronized progesterone vs. synthetic progestins) can have varying impacts on metabolic factors, cardiovascular risk, and mood. For instance, micronized progesterone, which is chemically identical to the natural hormone, is often associated with a lower risk of VTE compared to some synthetic progestins, allowing clinicians to tailor the combined regimen to minimize side effects and optimize the overall therapeutic profile.

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