In the present study, cyclic exposure to vaginally administered micronized progesterone over the short term failed to affect lipid profile in early and apparently healthy postmenopausal women. Several studies have evaluated the relationship between estrogen dose and/or route of administration and cardiovascular benefit-risk ratio of HT in postmenopausal women. More recently, observational studies began to draw attention to the impact of using specific types of progestin in combination with estrogen. However, there is a paucity of data derived from clinical trials to assess the effect of different progestogens on variables related to cardiovascular risk. Therefore, this work provides an important contribution toward clarifying the impact of combined micronized progesterone plus non-oral estrogen therapy.
Menopause is a risk factor for CVD because of the ensuing endogenous estrogen deficiency, which has a detrimental effect on cardiovascular function and metabolism. Even though there are biologically plausible mechanisms of cardiovascular protection against harm produced by estrogen therapy, recent clinical trials suggest that estrogen may be associated with cardiovascular risk rather than benefit in the postmenopause . However, reanalysis of these studies has indicated a possible protective window in which recent postmenopausal women in their sixth decade may benefit from HT [1, 13]. In addition, it has been speculated that the cardioprotective benefits of HT may be more evident in the early postmenopausal period , although this is a controversial issue . In the present study, the use of a sample of apparently healthy and relatively young (mean age of 51.3 ± 3 years) women who were postmenopausal for less than three years (22.2 ± 10 months) enabled us to more accurately demonstrate the neutral or beneficial effects of HT with both non-oral E2 alone or in combination with micronized progesterone- combined period.
Blood pressure levels remained unchanged after HT in the present sample. Previous studies have shown that non-oral estrogen therapy associated with micronized progesterone had no deleterious effects on blood pressure in normotensive and controlled hypertensive postmenopausal women [10, 16]. Estrogen increases the release of nitric oxide causing relaxation of smooth muscle cells and vasodilatation.
Progestins modulate the effects of estrogen on hepatic endocrine function through intrinsic androgenic properties. When co-administered with estrogen, progestogen may also have significant effects on body composition and metabolism because of its androgenic properties. The effects of HT on weight and body composition remain controversial . In our study, non-oral E2 therapy with or without micronized progesterone did not modify waist circumference, BMI or body weight. Additionally, the treatment did not interfere with glucose or insulin levels, and reduced total cholesterol and LDL-c, supporting the notion that micronized progesterone has a neutral effect on intermediate surrogate variables of cardiovascular risk . Dansuk et al.  evaluated the effects of five combinations of HT in postmenopausal women, including E2 alone and E2 associated with medroxyprogesterone (E2+MPA), noretisterone (E2+NETA), dydrogesterone (E2+DG) and micronized progesterone (E2+P). E2+NETA and E2+DG were found to improve insulin sensitivity after 3 months of treatment, whereas E2+P or E2 alone did not show such any effect in postmenopausal women.
It is well established that oral E2 therapy in conventional doses induces an increase in hsCRP, while transdermal E2 has either no effect on or even reduces hsCRP levels in postmenopausal women . Studies examining the effect of progestins on markers of inflammation have produced varying results . In the present study there was no worsening of hsCRP during HT with or without progesterone.
A limitation of this study is the short duration of treatment (6 months or less), since in clinical practice patients are usually treated for one year or more. Nevertheless, previous studies have reported significant changes in lipids and markers of endothelial function  after 4 to 12 weeks of HT. In addition, evidence suggests that there is a “critical period” in the first months of HT, related to greater inflammatory activation and higher thromboembolic risk events. Further studies of longer duration will be helpful to confirm our findings.