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Micronized Progesterone
and the Lipid Profile:

A Pilot Study Looking at the Effects
of Micronized Progesterone on the
Lipid Profile in HRT


Anil B. Pinto, MD

Terrence Harris, MD

Kelle H. Moley, MD

Nisha Vermani

Daniel B. Williams, MD


Department of OB/GYN

Division of Reproductive Endocrinology & Infertility

Washington University School of Medicine

St. Louis, MO


This study is supported by Solvay Pharmaceuticals, Inc.


KEY WORDS: micronized progesterone, lipid profile, endometrial effects



Objective: To compare lipid and endometrial effects of continuous micronized progesterone and medroxyprogesterone acetate hormone replacement therapy (HRT) on the lipid profiles of postmenopausal women with an intact uterus.

Design: This prospective, randomized, non-blinded trial was performed in a university based practice.

Patients: Postmenopausal women aged 40 to 75 years with an intact uterus and no contraindication to HRT.

Interventions: Patients were randomized to one of two groups: group 1 received conjugated equine estrogen (CEE), 0.625mg, plus continuous micronized progesterone, 100mg/day; group 2 received CEE, 0.625mg, plus continuous medroxyprogesterone acetate (MPA) 2.5mg/day.

Statistics: Data were analyzed using the SPSS (statistical package for the social sciences; SPSS Inc., Chicago, IL) (10.0) comprehensive system for analyzing data.

Main Outcome Measures: Serum lipid profiles were performed at baseline, 6 weeks, and 12 weeks; endometrial thickness was measured at baseline and 12 weeks; endometrial biopsy was performed at 12 weeks; bleeding patterns were recorded.

Results: Of 12 patients recruited, 10 successfully completed the study. The difference in total cholesterol at the end of the 12-week period was not significantly different between the two treatment groups (P=0.76). Additionally, no significant change was found in triglyceride levels in either group at the end of the study (P=0.41). No significant changes in HDL levels were observed in either treatment group. Decreased LDL levels were found in both treatment groups, but this change was not significant (P=0.18).

Conclusions: There appears to be no difference in the beneficial effect of HRT on the lipid profile in the two treatment groups.



Hormone replacement therapy (HRT) is known to have many cardiovascular benefits for postmenopausal women, and has been shown to significantly decrease the risk of coronary heart disease (CHD) in these women.1,2 Some of these effects are mediated by direct action of hormones on vascular smooth muscle,3,4 while others result from hormonally induced alterations in lipid metabolism.5-9

Most observational studies have demonstrated a significant role for HRT in both primary and secondary CHD prevention. Recently, however, the Heart and Estrogen/Progestin Replacement Study (HERS) found no demonstrated beneficial effect for estrogen and progestin on secondary prevention of adverse coronary events in women with a history of CHD. In fact, this study showed an increase in adverse events within the first year of therapy.10

Progestins have been added to HRT regimens in women with an intact uterus to negate the increased risk of endometrial cancer associated with unopposed estrogen.11 However, estrogen appears to be the hormone principally responsible for HRT's beneficial effects on the lipid profile,2,12-16 and some researchers have therefore suggested that the use of synthetic progestins may diminish these beneficial effects.9,12,17,18 In a study evaluating the effect of medroxyprogesterone acetate (MPA) on estrogen-induced lipid profile changes, Lobo et al18 found that beneficial changes in lipid levels occurred with both estrogen alone and in combination with progestin, but that these effects were greatest with estrogen alone. In an earlier study, Tufekci et al showed that the use of MPA did not significantly blunt the effect of estrogen on HDL levels.17

More recently, oral micronized progesterone has become available for use. A study by Fitzpatrick and Good19 confirmed that micronized progesterone has enhanced bioavailability and may therefore have potential as a component of HRT regimens. In another study, Fitzpatrick et al20 found that women who used HRT containing micronized progesterone had improved quality of life over those using MPA.

The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, as well as several other studies, concluded that estrogen (either alone or combined with progestin) significantly improved lipoprotein values over the 3-year study period.9,12,13,21,22 However, they also demonstrated that adding progestins to the regimen blunted the rise of high-density lipoprotein (HDL), and that this blunting effect was greater with continuous or cyclic MPA than with cyclic micronized progesterone.12 Several other studies have demonstrated different effects on lipid profiles for different progestins, negating some of the beneficial effects of estrogen.12,21 Conversely, Chen et al23 were unable to demonstrate a difference in these blunting effects between two different types of progestin in a study using cyclic progestin.

This pilot study seeks to compare the effects of continuous micronized progesterone and MPA on lipid profiles in postmenopausal women on HRT.




Postmenopausal women aged 40 to 75 years with an intact uterus were recruited. "Postmenopausal" was defined as having no natural menses for at least 1 year, or having no menses for greater than 6 months with a follicle stimulating hormone (FSH) value of greater than 40 mIU/mL and a serum estradiol of less than 40 mIU/mL. A total of 12 patients were recruited. Patients on HRT at the beginning of the study underwent a 4-week washout period (discontinuing all hormone therapy) prior to inclusion.24 Exclusion criteria included a history of cardiac disease (including myocardial infarction, coronary artery bypass graft, or uncontrolled hypertension), serum triglyceride levels greater than 300 mg/dL, endometrial hyperplasia with atypia, history of endometrial cancer, history of breast cancer, deep vein thrombosis, pulmonary embolism, or abnormal mammogram or PAP smear results.


Study Design

The study was conducted over a 3-month period. Eligible patients were randomized to one of two groups. Group 1 received esterified estrogen, 0.625 mg, plus continuous micronized progesterone, 100 mg/day. Group 2 received esterified estrogen, 0.625 mg, plus continuous medroxyprogesterone acetate (MPA), 2.5 mg/day. Patients underwent a complete history and physical examination at the initial study visit, including breast examination and pap smear if not done in the past year, a complete blood count, basic metabolic profile, liver function tests, and a fasting lipid profile. Transvaginal ultrasound (TVS) to assess the endometrial echo stripe (EMS) and mammogram (if not done in the past year) were also performed. Patients were given screening diaries to record bleeding patterns and any other significant symptoms such as hot flashes, breast tenderness, headaches, or mood swings.

Six weeks into the study, a fasting lipid profile was obtained. At the closeout visit at 12 weeks, the fasting lipid profile and TVS were repeated and an endometrial pipelle biopsy was performed. The primary end-points investigated were the lipid profile at baseline, 6 weeks, and 12 weeks, and the endometrial echo stripe at baseline and at 12 weeks. Secondary end points assessed were adverse symptoms, if any, experienced.


Data were analyzed using the SPSS (10.0) comprehensive system for analyzing data (Chicago). The lipid effects between the two treatment groups as well as within the individual groups were measured using independent sample T-tests. Un-paired T-tests were used to compare the demographic data between the two groups.



Of the 12 patients recruited for the study, 10 successfully completed it. One patient was omitted after failing to complete the requisite pre- and post-testing (this patient was on CEE and MPA). Another patient on CEE and micronized progesterone discontinued therapy due to fears associated with HRT.

The treatment groups showed no significant differences at baseline with respect to age, years since menopause, endometrial thickness, total cholesterol, LDL, or triglyceride levels. HDL cholesterol values were significantly higher at baseline in the micronized progesterone group.

The total cholesterol levels showed a downward trend in both treatment arms. These trends were not statistically significant. The difference in total cholesterol levels was significantly different between the two treatment groups at the end of the 12-week period (P<0.758). Additionally, no significant changes in triglyceride levels were found in either group at the end of the study period (Figure 1).

HDL levels were higher at baseline and at 12 weeks in the group receiving micronized progesterone than in patients receiving MPA (P<0.002). However, no significant changes in the HDL levels were observed within either treatment group during the study. Baseline HDL values were significantly higher in the CEE/micronized progesterone group (P<0.023). LDL cholesterol levels showed no difference within groups during the study, and no difference between groups at any point in the study (Figure 1).

No differences in bleeding patterns were found between the groups throughout the entire study. Only 2 patients reported spotting during the study. One patient in the MPA group reported spotting for 8 days and another patient in the micronized progesterone group reported irregular spotting for 5 days. Both patients were followed up with a clinic visit, transvaginal ultrasound, and endometrial biopsy. Both the endometrial biopsies were reported as atrophic.

No significant differences were found in endometrial thickness between or within the MPA versus micronized progesterone group at base line (3.4 2.0 mm and 4.0 0.55 mm, respectively) or at 12 weeks (4.6 0.96 mm and 4.75 2.1 mm, respectively). End of study endometrial biopsy results showed atrophic endometrium for all patients. Only 1 patient in the MPA group complained of other side effects, in this case, breast tenderness.


Previous studies have demonstrated a beneficial effect on the lipid profile from HRT.6,9,12,13,21,22 In addition, some studies have shown that the beneficial effect of estrogen is blunted by the addition of progesterone.9,12,17,18,23 Researchers have suggested that different progesterone regimens may have differing effects in terms of lipid protection.12,21 The PEPI Trial, which used both MPA and micronized progesterone, demonstrated that the blunting of the estrogen-induced rise in HDL seen with MPA decreased when MP was used.12 In a review of 10 years of clinical trials evaluating the effect of HRT on lipid parameters, Pickar et al21 found that the use of the more androgenic progestins (ie, norethindrone acetate and desogestrel) consistently produced a decrease in HDL levels, while less androgenic progestins produced an increase in these levels.

Chen et al23 have shown that neither MPA nor micronized progesterone have a distinct benefit over each other with respect to the lipid profiles. They compared CEE alone to CEE/MPA and CEE/micronized progesterone continuous regimens, and found that both cyclic MPA and micronized progesterone blunted the beneficial effects of estrogen on lipid profiles, but that neither progestin was more detrimental than the other in terms of lipid protection. The authors concluded that either progesterone could be used with equal effects. These results appear to contradict those of the PEPI trial,12 in which a cyclic progestin regimen was used. However, there are some differences in the HRT regimens. The total monthly doses of MPA and micronized progesterone were similar between the two studies (approximately 120 to 125 mg MPA and 2400 to 2500 mg micronized progesterone). However, Chen et al used 100 mg/day of micronized progesterone for 25 days of the month. Therefore, a shorter, lower-dose cyclic regimen of micronized progesterone may preserve a greater proportion of the beneficial effect of estrogen on the lipid profile than a lower dose continuous regimen. The authors also note that the lack of a difference seen in their study may in part be due to a shorter follow-up and the absence of a control group.

In our study, we found no apparent differences in the lipid profiles before and after treatment in either treatment groups. In a study spanning 2 years, Jensen et al25 investigated the effects of estradiol gel on serum lipids. They found that triglycerides were increased at the end of 12 months with estradiol gel alone and then decreased during the second year, when oral micronized progesterone was added. We did not see any significant changes in the triglyceride levels at the end of the study when compared to baseline levels in either group.

The PEPI trial12 showed a significant increase in HDL in all treatment regimens, and further showed that a CEE/micronized progesterone combination was superior to CEE/MPA in this regard. HDL levels increased for 6 to 12 months, then gradually decreased, though not to baseline levels. The LDL cholesterol decreased to its lowest levels by 6 to 12 months and did not change significantly thereafter, whereas the triglyceride levels increased comparably in all active treatment arms. Our study did not mirror the changes seen in the PEPI trial in terms of the HDL, LDL, or triglyceride values in both treatment arms. The total cholesterol decreased more in the MPA regimen (though not statistically significant), but we believe that this was due to the higher baseline total cholesterol value in this treatment group.

The PEPI trial suggested a benefit to using micronized progesterone over MPA with respect to lipid profiles.12 Our small study did not demonstrate this; however, it should be noted that the PEPI trial used a cyclic regimen of micronized progesterone, while we used continuous MPA and micronized progesterone. A review by Williams and Moley26 concluded that continuous progestin therapy appears to have no effect on estrogen-induced reduction of LDL-C and has little or no effect on HDL-C. It may well be that the factor contributing most to the blunting of lipid benefits is the cyclic use of these hormones rather than the type of progestin used. This may also explain the apparently contradictory findings of the PEPI trial and the previously described study by Chen et al,23 because the latter used a shorter continuous regimen of progestin.

Researchers have also suggested that progestogens may also blunt estrogen's favorable lipid protection. The 19-nortestosterone derivatives have been reported to increase LDL-C levels and reduce HDL-C levels, thus reversing the beneficial effects of estrogens.27 A few studies have suggested that natural progestogens do not appear to have any effect on plasma lipids.25,28

Unopposed estrogen is associated with increased risk of developing endometrial cancer,29,30 making it necessary to add a progestin to significantly reduce this risk.29,31 Our study showed no difference in terms of bleeding patterns or endometrial thickness in either arm at study close out, and all patients were reported to have an atrophic endometrium at study end. Since the adverse effect of progestogen cannot be completely excluded, adding the minimal dose of progestogen to HRT regimens to ensure endometrial protection seems reasonable.

Several reasons may explain the presence of trends rather than statistically significant changes in our study. First, our study included results for 12 patients, only 10 of which were included in the final analysis. Therefore, our results may be biased due to error secondary to a small sample size. In order to detect a 5% difference between groups, a sample size of 381 would be needed in each group to have 80% power. Secondly, it is possible that a longer study may have resulted in a different outcome. Natural progesterone is thought to be relatively inert in its effects on lipid metabolism, though this has not been extensively studied. Studies using cyclic regimens have suggested a beneficial effect of using micronized progesterone over MPA. We found no significant difference between either progestin used in a continuous combined HRT regimen. This is consistent with other studies that evaluated the lipid effects of continuous combined therapy.32,33 Certainly, further studies in this area are warranted.



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2. Espeland MA: Cardioprotective effects of postmenopausal hormone treatment. Am J Cardiol 82(10A):37S-39S, 1998.

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17. Tufekci M, Colak Z, Ozan H, et al: Effect of progestogens on estrogen-induced lipoprotein changes. Eur J Obstetrics Gynecol Reproductive Biol 49:169-174, 1993.

18. Lobo RA, Pickar JH, Wild RA, et al: Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. Obstet Gynecol 84(6):987-995, 1994.

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Figure 1. Cholesterol, triglyceride, HDL, and LDL levels according to treatment.

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