Natural progesterone research/references

Clinical studies continually demonstrate an effectiveness of bioidentical progesterone for symptom relief for menopause, hot flashes, anxiety, sleep disturbances, and mood swings. More and more research repeatedly indicates that adequate progesterone is needed for fertility, cardiovascular health, nervous system function, and bone health, and also protects against the effects of too much estrogen for women using estrogen therapy. Bioidentical progesterone has historically been used to support regular menstruation and provide biological support for fertility. 

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natural progesterone & menopause

Randolph JF, Sowers MF, Bondarenko I, Gold EB, Greendale GA, Bromberger JT, Brockwell SE, Matthews K.
The relationship of longitudinal change in reproductive hormones and vasomotor symptoms during the menopausal transition.J Clin Endocrinol Metab. 2005 Nov;90(11):6106-12.

Vasomotor symptoms are experienced by 65-76% of women going through menopause.This study examined longitudinal changes in estradiol, FSH, testosterone, DHEA, sex hormone binding globulin, free estrogen index and free testosterone index, and found that only FSH levels were associated with the prevalence and frequency of vasomotor symptoms.

Stephenson K, Price C, Kurdowska A, Neuenschwander P, Stephenson J, Pinson B,Stephenson D, Alfred D, Krupa A, Mahoney D, Zava D, Bevan M.Topical progesterone cream does not increase thrombotic and inflammatory factors in postmenopausal women. Presented at the 46th Annual Meeting of the American Society of Hematology, San Diego, December 4-7, 2004.Blood 2004; 104(11): Abstract 5318.

No change in any of the thrombotic or inflammatory markers studied (total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, PAI-1, CRP, TNFa, and IL-6) was observed, despite significant relief of vasomotor symptoms compared to placebo, in 30 postmenopausal women receiving 20 mg/day progesterone cream for 4 weeks.From this study the authors conclude that administration of topical progesterone cream at a daily dose of 20 mg significantly relieves menopausal symptoms in postmenopausal women without adversely altering prothrombotic potential. Since the thrombotic complications that are typically observed with conventional hormone replacement therapy, and have led to an increase in stroke,do not seem to occur with topical progesterone, this treatment should be seriously considered as an effective and safe alternative clinical therapy for women suffering from menopausal symptoms. 

Montplaisir J, Lorrain J, Denesle R, Petit D. Sleep in menopause: differential effects of two forms of hormone replacement therapy. Menopause 2001; 8(1):10-16.

This randomized clinical trial compared the effects of conjugated equine estrogen (CEE) and medroxyprogesterone acetate to CEE and oral micronized progesterone. Twenty-one postmenopausal women were studied in a sleep lab, with results demonstrating an improvement in subjective measures of menopausal symptoms and sleep in both groups. The group receiving natural progesterone had significantly improved sleep efficiency, whereas the medroxyprogesterone acetate group did not, suggesting that the former might better improve sleep in postmenopausal women. 

Ryan N, Rosner A. Quality of life (QOL) and costs associated with micronized progesterone and medroxyprogesterone acetate in hormone replacement therapy for non-hysterectomized, postmenopausal women. Clin Ther 2001 Jul;23(7):1099-115.

This prospective, multicenter, randomized, parallel-group study enrolled 182 postmenopausal women 45 to 65 years of age and evaluated the quality of life and menopausal symptoms associated with the use of medroxyprogesterone acetate vs oral micronized progesterone when used as a part of a regular hormone replacement therapy. Menopausal symptoms improved in both groups from baseline to 9 months, as did QOL measures. In addition, patients using micronized progesterone had specific improvements in the areas of cognition and menstrual problems whereas the patients using MPA did not. Micronized progesterone was seen as an effective, cost-comparable alternative to MPA as well as being better tolerated. 

Fitzpatrick LA, Pace C, Wiita B. Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey. J Women Health Gend Based Med 2000 May;9(4):381-7.

A cross-sectional survey was conducted to examine quality of life (QOL) related to physiological, somatic, and vasomotor effects of switching progestogen treatment from medroxyprogesterone acetate (MPA) to micronized progesterone in postmenopausal women already using hormone replacement therapy (HRT). One hundred seventy-six women who were currently using hormone replacement therapy (HRT) containing micronized progesterone for 1-6 months and had previously received HRT containing MPA were surveyed to assess QOL. Women using micronized progesterone-containing HRT experienced significant improvement in vasomotor symptoms, anxiety, somatic complaints and depressive symptoms. Women reported improved control of menopausal symptoms and perceptions of their vaginal bleeding patterns while on the micronized progesterone-containing regimen. Approximately 80% of women reported satisfaction with the progesterone-containing therapy. A micronized progesterone-containing HRT therapy offers the potential for improved QOL with respect to menopausal symptoms.

Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999 Aug;94(2):225-8.

In this randomized controlled trial, 102 menopausal women were treated with topical progesterone (Pro-gest®, 20 mg daily) or placebo and monitored for 1 year. Improvement in vasomotor symptoms was seen in 83% of the women in the treatment group who had experienced hot flashes, compared to 19% in the placebo group (p< .001). There was no difference noted in bone mineral densities between groups after one year. All women studied received a daily multivitamin and 1200 mg calcium. 

Wetzel W. Micronized progesterone: a new option for women's health care. Nurse Pract 1999 May;24(5):62-6, 71, 75-6.

This paper discusses the use of micronized progesterone as a safe, effective, and well-tolerated therapy and reviews indications for use. It also includes case studies and issues of patient compliance and the need for an individualized treatment plan for women receiving hormone therapy. 

Sherwin BB. Progestogens used in menopause. Side effects, mood and quality of life. J Reprod Med 1999 Feb;44(2 Suppl):227-32.

This review summarizes the effects of progesterone on mood and other brain functions. Progesterone receptors are present in many of the same areas of the brain as estrogen receptors, including the limbic system and hypothalamus. The limbic system plays a prominent role in regulating mood and emotion. As a comparison, progesterone decreases brain excitability, while estrogens increase it. This relates to why women with epilepsy have a higher frequency of seizures during the part of the cycle when estrogen levels are high, and a reduced frequency when progesterone levels are high. Estrogen and progesterone may also have differing effects on MAO, thereby affecting concentration of serotonin (a mood elevator) in the brain.

natural progesterone: menstrual health, pms, infertility & pregnancy  

Yonkers K. Review:
 progesterone or progestogens lead to a marginal reduction in premenstrual syndrome symptoms.Evid Based Ment Health. 2002 May;5(2):56.

The author conducted an analysis of randomized, double blind, placebo-controlled studies of progesterone or progestins in women diagnosed with PMS.Oral micronized progesterone and the progestogens MPA, norethisterone and dydrogesterone, all showed a marginal benefit over placebo in symptom reduction. 

Shantha S, Brooks-Gunn J, Locke RJ, Warren MP. Natural vaginal progesterone is associated with minimal psychological side effects: a preliminary study. J Women Health Gend Based Med 2001 Dec;10(10):991-7.

This 3 month, multicenter randomized study evaluated the psychological side effects of a vaginally applied progesterone gel in reproductive aged women treated for hypothalamic amenorrhea or premature ovarian failure. No differences were noted in psychometric measures as evaluated by the Hopkins Symptom Checklist. Natural progesterone in a vaginal gel can be an effective treatment for women requiring hormone therapy. 

Wyatt K, Dimmock P, Jones P, Obhrai M, O'Brien S. Efficacy of progesterone and progestogens in management of premenstrual syndrome: systematic review. BMJ. 2001 Oct 6;323(7316):776-80.

This systematic review of published studies of progesterone or progestogens for treatment of PMS found a small positive effect of oral micronized progesterone over placebo in the 3 trials that studied this.No published studies of progesterone cream were found.A statistically, but not clinically, significant improvement was seen with progestogen treatment.

Sofuoglu M, Babb DA, Hatsukami DK. Progesterone treatment during the early follicular phase of the menstrual cycle: effects on smoking behavior in women. Pharmacol Biochem Behav 2001 May-Jun;69(1-2):299-304.

In this unique randomized controlled study, administration of progesterone (200 mg oral) demonstrated a decrease in craving for and subjective effects of cigarette smoking in female smokers. With progesterone treatment, there was a noted trend to decrease smoking.

Fitzpatrick LA, Good A. Micronized progesterone: clinical indications and comparison with current treatments. Fertil Steril 1999 Sep;72(3):389-97.

The literature reviewed in this tutorial indicates a potential use for oral micronized progesterone for the treatment of secondary amenorrhea, dysfunctional uterine bleeding, luteal phase disorders, premenopausal bleeding disorders, and as a component of hormone replacement therapy that may provide a better safety profile than commonly utilized synthetic progestins. 

Massai R, Miranda P, et al. Preregistration study on the safety and contraceptive efficacy of a progesterone-releasing vaginal ring in Chilean nursing women. Contraception 1999 Jul;60(1):9-14.

In this long-term controlled study, the safety and efficacy of a progesterone-releasing vaginal contraceptive device was compared to that of the copper-T 380A IUD in nursing mothers. There was no difference in breastfeeding performance or infant growth between groups. The participants using the progesterone-releasing ring had a longer period of lactational amenorrhea than did the group using the copper T. Women were tracked for over 2000 women-months of exposure in both groups. The Chilean government found the progesterone-releasing ring to be a safe and effective contraceptive alternative. 

Hajek Z, Uhlir M. [Micronized progesterone in the treatment of imminent necrosis of a myoma during pregnancy. Ultrasound changes during treatment] Ceska Gynekol 1999 Jun;64(3):189-92. [Article in Czech]

Progesterone has a role in increasing blood flow to the uterus during pregnancy. As such, these researchers studied the effect of progesterone treatment to resolve imminent necrosis of a myoma in two cases. Both resolved within several days following oral and vaginal doses of progesterone (300-600 mg/day). Both women went on to deliver healthy, full-term infants.

Pouly JL, Bassil S, Frydman R, et al. Luteal support after in-vitro fertilization: Crinone®, a sustained release vaginal progesterone gel, versus Utrogestan, an oral micronized progesterone. Human Reprod 1996;11:2085-89.

90 mg of vaginal estrogen gel daily was compared to 300 mg oral progesterone daily in a randomized open-label trial of 283 IVF patients. Delivery rates, safety parameters, frequency of spontaneous abortion, ratio of newborn babies to embryo transfer were nearly identical for both groups. The oral progesterone group reported more drowsiness.

Nappi C, Affinito P. Double-blind controlled trial of progesterone vaginal cream treatment for cyclical mastodynia in women with benign breast disease. J Endocrin Invest 1994;15(11):801-6.

Eighty regularly menstruating women with mastodynia were studied to evaluate the clinical effectiveness of vaginally administered micronized progesterone. Subjects were randomly assigned to one of two groups, with all participating in a control cycle prior to treatment. One group received 4 grams of vaginal cream containing 2.5% natural progesterone for six cycles from day 19 to day 25 of the cycle. The other group was similarly treated with placebo. Both subjective reporting on a daily basis and clinical examination revealed a significant reduction in breast pain, defined as 50% reduction, in 64.9% of subjects receiving progesterone and 22.2% of subjects receiving placebo. Effects of breast nodularity were not significant. No side effects were detected.

Martorano JT, Ahlgrimm M, Meyers D. Differentiating between natural progesterone and synthetic progestogens: clinical implications for PMS management. Comprehensive Therapy 1993; 19(3):96-8.

Clinical observations demonstrate that patients suffering from PMS respond to treatment with natural progesterone, whereas synthetic progestins may exacerbate the condition. The authors review the differences between natural progesterone and synthetic progestins. 

Saarikoski S, Yliskoski M, Penttila I. Sequential use of norethisterone and natural progesterone in pre-menopausal bleeding disorders. Maturitas 1990 Jun;12(2):89-97.

This randomized controlled study evaluated the effects of norethisterone (NET) and micronized progesterone (MP) on bleeding disorders in pre-menopausal women. 80 patients were randomized to the trial and all were found via endometrial morphology to need progestogen therapy. They were subsequently treated with NET or MP. In both treatment groups, hyperplastic changes disappeared during the first three cycles, with the duration of treatment being 6 months. NET decreased follicle-stimulating hormone, luteinizing hormone, estradiol and sex-hormone-binding globulin levels (P < 0.001) whereas no changes were seen during MP treatment. High-density-lipoprotein cholesterol and triglyceride levels were also lowered by NET (P< 0.001-0.02) slightly decreased phospholipids. MP treatment had no effect on lipid profiles suggesting it may be a preferred progestogen for the treatment of bleeding disorders. 

Sitruk-Ware R, Bricaire C, De Lignieres B, Yaneva H, Mauvais-Jarvis P. Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications--a review. Contraception 1987 Oct; 36(4): 373-402.

This paper reviews the effects and benefits of oral micronized progesterone. Progesterone exhibits anti-estrogenic effects, anti-androgenic effects, and anti-mineralocorticoid effects in addition to its progestational effects. No side effects have been reported for micronized progesterone with respect to lipid profile, coagulation, or blood pressure, leading the authors to recommend micronized progesterone as suitable for treatment of PMS, menopause, irregular cycles, and pregnancy maintenance. 

Dennerstein L, Spencer-Gardner C, Gotts G, Brown JB, Smith MA, Burrows GD. Progesterone and the premenstrual syndrome: a double blind crossover trial. Br Med J (Clin Res Ed) 1985 Jun 1; 290(6482): 1617-21.

In this double-blind, placebo-controlled, randomized, crossover trial, oral micronized progesterone demonstrated effectiveness in alleviating premenstrual complaints. Twenty-three women completed a Beck, et al depression inventory, Moos’s menstrual distress questionnaire, Spielberger, et al state anxiety inventory, and daily symptom diary before and during each treatment. There was an overall benefit of treatment for all variables, except positive moods, restlessness, and interest in sex. For most parameters, maximum benefit was seen within the first month of treatment, demonstrating an effectiveness of progesterone as a viable treatment option for women with PMS. 

Ferre F, Uzan M, Janssens Y, Tanguy G, Jolivet A, Breuiller M, Sureau C, Cedard L. Oral administration of micronized natural progesterone in late human pregnancy. Effects on progesterone and estrogen concentrations in the plasma, placenta, and myometrium. Am J Obstet Gynecol 1984 Jan 1; 148(1): 26-34.

Levels of progesterone, 17 beta-estradiol, and estrone were measured in the plasma, in the placenta, and at different sites in myometrium following a single dose of micronized oral progesterone administered to 15 pregnant women immediately prior to elective cesarean section.In comparison to a control group, progesterone levels in the treated women increased in the plasma and myometrium 150 minutes after administration. Placenta progesterone levels did not demonstrate any change. No change was seen in 17 beta-estradiol levels in the plasma or the myometrium, however placental levels were increased. Estrone levels were decreased in the myometrium and in the placenta, and unchanged in the plasma. 

Dalton K. The effects of progesterone and progestogens on the foetus. Neuropharmacology 1981; 20:1267-9.

This article looks at the differing effects of progesterone and synthetic progestogens on the fetus. Of note in this article is evidence that progesterone supplementation may reduce episodes of pre-eclampsia. Synthetic progestogen supplementation during pregnancy may produce a variety of side effects. Several references are made to articles documenting cases of masculinization of external genitalia in female babies. There are two known cases of true hermaphroditism and several cases of behavioral problems developing in adolescent girls whose mothers took oral synthetic progestogens during pregnancy. More problematic may be administration of oral estrogen-progestogen preparations. Side effects may include spina bifida, esophageal anomalies, heart defects and limb reduction deformities. 

Dalton K. Prenatal progesterone and educational attainments. British Journal of Psychiatry 1976; 126:438-42.

This study compares educational attainments of 34 children whose mothers received prenatal progesterone with 37 normal and 12 toxemic controls. Results at ages 17-24 showed that progesterone children were more likely to continue schooling after 16 years, a higher number left school with ‘O’ and ‘A’ level grades and more obtained entrance to university. The best academic results were found for children whose mothers had received over 5 grams of progesterone for a minimum of eight weeks, with treatment beginning before week sixteen.

natural progesterone, the brain, & the nervous system

Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG.ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury.Ann Emerg Med 2006 Sep 28; [Epub ahead of print].

A neuroprotective effect of progesterone was observed in this randomized, placebo-controlled trial of very high dose, intravenous progesterone therapy given for 3 days after acute traumatic brain injury.Only 13% of the patients died within 30 days after injury in the progesterone group, compared with 30% of the placebo group, and the progesterone group was more likely to have a moderate to good functional outcome after 30 days than the placebo group.Even at the extremely high dose used, no serious adverse events were seen with progesterone.

Gibson CL, Murphy SP. Progesterone enhances functional recovery after middle cerebral artery occlusion in male mice. J Cereb Blood Flow Metab. 2004 Jul;24(7):805-13.

Differences in outcomes following ischemia have been noted between men and women, and this is thought to be attributed to sex steroids. This study investigated the potential benefits of progesterone administration after focal cerebral ischemia of the middle cerebral artery of male mice. Male mice undergoing 60-minute middle cerebral artery occlusion (MCAO) received either progesterone or vehicle following occlusion. The mice receiving progesterone had significantly reduced lesion volume (p< 0.05) when compared with the vehicle treated mice (control). Progesterone treatment also improved survival rate, weight recovery, and motor ability when compared to the control group. In addition, mice treated with progesterone demonstrated motor ability comparable to mice that did not undergo MCAO. The authors suggest the need to further investigate the mechanisms of progesterone action on recovery from cerebral injury.

Schumacher M, Guennoun R, Robert F, Carelli C, Gago N, Ghoumari A, Gonzalez Deniselle MC, Gonzalez SL, Ibanez C, Labombarda F, Coirini H, Baulieu EE, De Nicola AF. Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination. Growth Horm IGF Res. 2004 Jun;14 Suppl A:S18-33.

This paper reviews of the effects of progesterone as an autocrine/paracrine hormone in the brain. The brain, spinal cord and peripheral nerves all synthesize progesterone from the precursor, pregnenolone. Macroglial cells, including astrocytes, oligodendroglial cells and Schwann cells, also have the capacity to synthesize progesterone. This production is regulated by cellular interactions. Recent research has suggested the role progesterone plays in the brain is likely a significant one, supporting the viability of neurons and the formation of myelin sheaths. In mice and rat studies, progesterone also demonstrated a neuroprotective effect. These actions of progesterone suggest viable therapeutic possibilities for the prevention and treatment of neurodegenerative diseases, as well as for repair processes and for preserving cognitive functions with age. 

Grossman KJ, Goss CW, Stein DG. Effects of progesterone on the inflammatory response to brain injury in the rat. Brain Res. 2004 May 15;1008(1):29-39.

Progesterone has a known anti-inflammatory effect. In this study, male rats treated with progesterone (4 mg/kg) and/or vehicle, were examined with respect to cellular inflammatory response to frontal cortex injury on postsurgical days 1, 3, 5, 7 and 9. The treated mice suffered significantly less edema than untreated mice, as well as showed an increase in the accumulation of activated microglia, demonstrating a neuroprotective effect on the rat brain.

Cummings JA, Brizendine L. Comparison of physical and emotional side effects of progesterone or medroxyprogesterone in early postmenopausal women. Menopause 2002 Jul-Aug;9(4):253-63.

Twenty-three early postmenopausal women were randomized to either medroxyprogesterone acetate (MPA) or oral micronized progesterone combined with conjugated equine estrogens (CEE) and followed for 91 days in a sequence of treatments. None of the hormone treatments had any noticeable effect on mood. Participants using MPA experienced more breast tenderness and bleeding than those using progesterone. This study debunks the belief that progesterone depresses mood in healthy individuals.

de Wit H, Schmitt L, Purdy R, Hauger R. Effects of acute progesterone administration in healthy postmenopausal women and normally-cycling women. Psychoneuroendocrinology 2001 Oct;26(7):697-710.

This randomized controlled study investigated the effects of acute progesterone administration (25, 50, 100 mg, intramuscularly, 1 dose/wk) on mood. Contrary to the investigators’ expectations, very few unwanted behavioral effects were noted, and only in the highest dose (100 mg) did women slightly increase their self-rating of “sluggishness”.

Baulieu E, Schumacher M. Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination. Steroids 2000 Oct-Nov;65(10-11):605-12.

This paper reviews the effects of progesterone on the brain, with special focus on its role in the formation of the myelin sheath surrounding nerve fibers. Other roles of progesterone in the brain include activating GABA receptors, which induces a calming effect.

Mahesh VB, Brann DW, and Hendry LB. Diverse modes of action of progesterone and its metabolites. J Steroid Biochem Molec Biol 1996;56(1-6):209-219.

A review of the actions of progesterone and its metabolites demonstrates physiological significance in such biological activities as may have importance in the regulation of stress, post-partum depression, memory, cognition, PMS, and depression, to name a few.

Arafat ES, Hargrove JT, Maxson WS, Desiderio DM, Wentz AC, Andersen RN. Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites. Am J Obstet Gynecol 1988 Nov; 159(5): 1203-9.

This small pilot study evaluated progesterone and its metabolites following administration of oral micronized progesterone in eight postmenopausal women. Progesterone and its metabolites were measured in serum extracts by radioimmunoassay and gas chromatography-mass spectrometry. Evaluation of serial blood samples showed elevated levels of serum progesterone and its metabolites from baseline, reaching a peak between 2 and 6 hours after oral administration. The following compounds: progesterone, 5 beta-pregnan-3 alpha, 5 alpha-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha-ol-20-one, 20 beta-diol, and 5 beta-pregnan-3 alpha-ol-11,20-dione, were identified. These compounds have reported anesthetic qualities, which may contribute to the sedative and hypnotic effects seen with oral administration of progesterone. The authors reported that, in one subject, 400 mg of oral micronized progesterone induced a hypnotic state lasting approximately 2 hours. 

natural progesterone safety

Stephenson K, Price C, Kurdowska A, Neuenschwander P, Stephenson J, Pinson B, Stephenson D, Alfred D, Krupa A, Mahoney D, Zava D, Bevan M.
Topical progesterone cream does not increase thrombotic and inflammatory factors in postmenopausal women.Presented at the 46th Annual Meeting of the American Society of Hematology, San Diego, December 4-7, 2004.Blood 2004; 104(11): Abstract 5318.

No change in any of the thrombotic or inflammatory markers studied (total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, PAI-1, CRP, TNFa, and IL-6) was observed, despite significant symptomatic improvement compared to placebo, in 30 women receiving 20 mg/day progesterone cream for 4 weeks. 

Bagis T, Gokcel A, Zeyneloglu HB, Tarim E, Kilicdag EB, Haydardedeoglu B. The effects of short-term medroxyprogesterone acetate and micronized progesterone on glucose metabolism and lipid profiles in patients with polycystic ovary syndrome: a prospective randomized study. J Clin Endocrinol Metab 2002 Oct;87(10):4536-40. 

This randomized prospective study evaluated and compared the effects of ten days treatment with oral and vaginal progesterone (MP) and medroxyprogesterone acetate (MPA) on glucose metabolism, lipid profiles, and hormonal parameters in 28 patients with polycystic ovary syndrome (PCOS). Oral MPA and oral MP decreased LH (P = 0.028, P = 0.009, respectively) and total testosterone (P = 0.013, P = 0.037, respectively) levels. There was no change in hormonal parameters with vaginal MP. Basal insulin decreased (P = 0.021) and insulin sensitivity increased significantly in the oral MPA group. Low density lipoprotein cholesterol (LDL) and lipoprotein (a) levels decreased only in the MPA group. This study concluded that MPA and oral MP may reduce insulin sensitivity in patients with PCOS. Vaginal MP had no effect on glucose metabolism and lipid profiles. 

Shantha S, Brooks-Gunn J, Locke RJ, Warren MP. Natural vaginal progesterone is associated with minimal psychological side effects: a preliminary study. J Women Health Gend Based Med 2001 Dec;10(10):991-7. 

This 3 month, multicenter randomized study evaluated the psychological side effects of a vaginally applied progesterone gel in reproductive aged women treated for hypothalamic amenorrhea or premature ovarian failure. No differences were noted in psychometric measures as evaluated by the Hopkins Symptom Checklist. Natural progesterone in a vaginal gel can be an effective treatment for women requiring hormone therapy. 

de Ziegler D, Fanchin R. Progesterone and progestins: applications in gynecology. Steroids 2000 Oct-Nov;65(10-11):671-9.

This paper reviews the use of a transvaginal progesterone gel as a viable option to other routes of application of natural progesterone (intramuscular, oral micronized), and offered it as a viable option to synthetic progestins given the low incidence of side effects noted in existing studies. 

Sitruk-Ware R. Progestins and cardiovascular risk markers. Steroids 2000 Oct-Nov;65(10-11):651-8.

This article reviews the effects of various synthetic progestins and progesterone on cardiovascular health. Many synthetic progestins, especially 19-nortestosterone and some 17-hyroxyprogesterones, have negative effects on cardiovascular risk factors, whereas natural progesterone does not. Further studies utilizing natural and other steroids should be considered. 

Fitzpatrick LA, Good A. Micronized progesterone: clinical indications and comparison with current treatments. Fertil Steril 1999 Sep;72(3):389-97. 

The literature reviewed in this tutorial indicates a potential use for oral micronized progesterone for the treatment of secondary amenorrhea, dysfunctional uterine bleeding, luteal phase disorders, premenopausal bleeding disorders, and as a component of hormone replacement therapy that may provide a better safety profile than commonly utilized synthetic progestins. 

Darj E, Axelsson O, et al. Liver Metabolism During Treatment with Estradiol and Natural Progesterone. Gynecological Endocrinology June 1993; 7(2):111-4.

Thirty postmenopausal women were treated daily for four months with 2 mg micronized 17 beta-estradiol and micronized progesterone orally in doses of 50, 100 and 200 mg daily. Serum concentrations of sex hormone-binding globulin (SHBG), corticosteroid binding globulin (CBG), ceruloplasmin, lipoprotein A and liver enzymes were measured. Serum SHBG and CBG increased during treatment with a weak association shown between progesterone and serum CBG. Levels of lipoprotein A and liver enzymes did not change, concluding that natural progesterone supplementation in postmenopausal women does not appear to cause any side effects to the liver. 

Ottosson UB, Johansson BG, et al. Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: A comparison between progestogens and natural progesterone. American Journal of Obstetrics and Gynecology 1993 Mar;151(6): 746-50.

Fifty-eight postmenopausal women were followed with respect to subfractions of high-density lipoprotein during 3 cycles of unopposed estrogen. The women received either levonorgestrel, medroxyprogesterone acetate, or natural progesterone during the last ten days of the treatment period. Both progestogens significantly lowered HDL cholesterol, whereas natural progesterone had no effect on HDL levels.

serenity progesterone cream