First, in general, people seem to do best injecting EV on a weekly basis or at most, every 10 days. I inject mine every 5 days.
Contraception. 1980 Apr;21(4):415-24.
"The average duration of elevated estrogen levels was shortest in the benzoate group (4-5 days) followed by the valerate (7-8 days) and cypionate (approximately 11 days). In none of the subjects studied were elevated estradiol and/or estrone levels encountered 2 weeks after the injection of the various esters."
In this study, peak levels were attained, on average, on day 2 with EV and subsequently, began dropping, especially after day 4. Looking at the graphs, it appears to me peak levels were also on day 2 with estradiol cypionate but diminished much more gradually over the remaining days, resulting in steadier levels.
Maturitas, 4 (1982) 315-324
"Because of the delayed release of the steroid ester from the intramuscular depot referred to earlier the blood level does not reach its maximum for 3-5 days, after which it falls slowly, with a half-life of 4-5 days, to the 17B-oestradiol concentrations measured before the treatment."
Horm Res 1983;17:84–89
"From the course of the levels, which were different in the 3 subjects, a half-life of 4-5 days was estimated for 17B-estradiol. On on average the individually measured baseline values were reached 14 +/- 2 days after administration"
In this study, levels peaked at day 1-2 in one subject, at around day 4 for another and finally, at around day 7-8 for the remaining subject. Levels appeared to be more steady in the latter 2 subjects.
Int J Clin Pharmacol Ther. 2012 Feb;50(2):100-17.
"The medians with minimum and maximum values of the net terminal elimination half-lives (...) of E2 were calculated as 85.7 h (29.58 - 148.17 h) and 80.9 h (52.82 - 171.63 h) after test and reference respectively."
Second, regarding medroxyprogesterone acetate,
1) It may, in some, increase anxiety, irritability, depression, even make some suicidal.
Natural Progesterone: What Role in Women's Health Care?
Whether it's right for your patient depends on the specific setting
JANE L. MURRAY, MD
"The 1998 Physicians' Desk Reference indicates that medroxyprogesterone acetate should be used cautiously in patients with a history of depression; if the depression recurs or worsens, the progestin should be stopped."
J Womens Health Gend Based Med. 2000 May;9(4):381-7
"When compared with the MPA-containing
regimen, women using micronized progesterone-containing HRT
experienced significant improvement in vasomotor symptoms, somatic
complaints, and anxiety and depressive symptoms."
CLIMACTERIC 2005;8(Suppl 1):3–63
"It has been shown that MPA may impair the beneficial effects of CEE on depressive mood and other psychological symptoms in postmenopausal women"
CEE is conjugated equine estrogens (Premarin)
J Clin Endocrinol Metab. 2004 Jun;89(6):2998-3006.
"These findings suggest that MPA antagonizes certain behavioral effects of E2 that may be beneficial to women, and that it does so more profoundly or in ways that endogenous P4 does not. The marked increase in aggression seen during MPA treatment suggests that production of negative affect may be a particularly serious side effect of MPA."
E2 is estradiol and P4 is bio-identical progesterone.
Maturitas. 2015 Mar 9. pii: S0378-5122(15)00314-X.
"In a cross-sectional study of 176 women who had previously switched from HT containing MPA to HT containing micronized progesterone, 71% had switched because of the better side effect profile, 35% because they believed the long-term risks would be fewer, and 23% because of intolerance to MPA [21]. When evaluated at 1 to 6 months after switching, the women experienced significantly better quality of life, including less depression and anxiety, than with MPA (both P < 0.001) [21]. Patient satisfaction questionnaires also indicated that women preferred micronized progesterone over their previous regimen for better symptom control and fewer adverse effects (P < 0.001) [21]. In the study by Ryan and Rosner of CEE with either progesterone or MPA, results on the Women's Health Questionnaire showed a significant group-by-visit interaction indicating better quality of life in the progesterone group in the cognitive difficulties domain (P = 0.015) [19]. »
Journal of the Gay and Lesbian Medical Association, Vol. 4, No. 4, 2000
"Micronized progesterone (Prometrium) is advantageous because it has a more favorable side effect profile (anxiety and irritability) than medroxyprogesterone."
Trends in Endocrinology and Metabolism
Volume 11, Issue 2, 1 March 2000, Pages 69–71
"Curiously, addition of the synthetic progestin, medroxyprogesterone, blocked the modulating effects of oestrogen on serotonin activity, while natural progesterone did not."
2) It is mildly androgenic whereas progesterone is not. That's why it is never given to pregnant women whereas progesterone is for prevention of miscarriage.
CLIMACTERIC 2005;8(Suppl 1):3–63
"MPA has no antiandrogenic effect, but weak androgenic properties."
Contraception. 1987 Oct;36(4):373-402.
"Progesterone (P), the natural hormone, binds to its specific
receptors to induce specific progestational effects. In addition to
this binding, P is able to interfere with the binding sites of other
steroids. Therefore the natural hormone exhibits an anti-estrogenic
activity, and anti-androgenic activity and also exerts anti-
mineralocorticoid effects. For a long time progesterone could not be
used in clinical applications because of a rapid liver inactivation
after oral administration. An oral micronized preparation of
progesterone is now available which produces adequate plasma and
tissue levels of progesterone. The preparation reproduces the anti-
estrogenic effect of the natural hormone on the endometrium . It also
reproduces the anti-mineralocorticoid effect and has no androgenic action.
No side effects have been reported as far as lipids profile, coagulation factors and blood
pressure are concerned."
Maturitas 46S1 (2003) S7–S16
"some of the older-generation progestins such as MPA, norethindrone acetate, norethindrone, and levonorgestrel, which bind with relatively high affinity to the AR, have been reported to act as agonists or partial agonists in some contexts, unlike progesterone (Table 4) (77–86)"
"MPA, norethindrone, levonorgestrel, and gestodene, but not dienogest, exhibit strong to weak partial agonist activity for AR-mediated transactivation via androgen response elements (77, 105, 178–180), whereas dienogest, trimegestone, drospirenone, and progesterone, but not MPA or norethindrone, can antagonize DHT-mediated transactivation via the AR (97, 178, 179)."
"The findings that some progestins like MPA, norethindrone, levonorgestrel, and gestodene bind to the AR with relatively high affinity and exhibit partial agonist activity via the AR in cell lines, and androgenic effects in rats, suggest that these progestins may result in AR-mediated androgenic genomic effects in women on HT."
Experimental and Clinical Psychopharmacology
2007, Vol. 15, No. 5, 427–444
Progesterone: Review of Safety for Clinical Studies
"Synthetic progestins marketed as Provera, PremPro, and Cycrin are widely used but may produce a number of significant side effects, such as (...) increased androgenicity."
3) It increases breast cancer risk vs progesterone that does not. Has been associated with increased risk in the famous 2003 WHI study.
CLIMACTERIC 2005;8(Suppl 1):3–63
"Recent epidemiological studies found an increase in the relative risk by 20–30% during treatment with CEE/MPA" (risk of breast cancer)
"The nearly significant reduction in breast cancer incidence in women treated with CEE alone"
Med Hypotheses. 2001 Feb;56(2):213-6.
"Recent epidemiology indicates that unopposed oral estrogen
replacement therapy has a surprisingly small impact on breast cancer
risk--little if any in overweight women--whereas combined regimens
featuring synthetic progestins are attended by a much larger
increase in this risk."
Int J Cancer. 2005 Apr 10;114(3):448-54.
"(...)Our study shows an increased risk of breast cancer associated
with HRT use. It indicates that the association between HRT use
and breast cancer risk most likely varies according to the type of
progestogen used. There was no or little increase in risk with
estrogens used alone or combined with micronized progesterone,
at least when used for short periods. The increase in risk reached
significance when estrogens were combined with synthetic progestins
and was significantly greater than when combined with
micronized progesterone."
J Steroid Biochem Mol Biol. 2005 Jul;96(2):95-108.
"Controlled studies and most observational studies published over
the last 5 years suggest that the addition of synthetic progestins
to estrogen in hormone replacement therapy (HRT), particularly in
continuous-combined regimen, increases the breast cancer (BC) risk
compared to estrogen alone. By contrast, a recent study suggests
that the addition of natural progesterone in cyclic regimens does
not affect BC risk. This finding is consistent with in vivo data
suggesting that progesterone does not have a detrimental effect on
breast tissue."
Climacteric. 2012 Apr;15 Suppl 1:3-10.
"Unlike some progestogens, progesterone is also not associated with an increased risk of VTE, or with an increased risk of breast cancer."
PLoS One. 2013 Nov 1;8(11)
Risk of breast cancer by type of menopausal hormone therapy: a case-control study among post-menopausal women in France.
"This study confirms differential effects on breast cancer risk of progestagens and regimens specifically used in France. Formulation of EP therapies containing natural progesterone, frequently prescribed in France, was not associated with increased risk of breast cancer"
Maturitas 46S1 (2003) S7–S16
Classification and pharmacology of progestins
"In particular, AR-mediated genomic effects by MPA or other AR partial agonists have been suggested to play a role in increasing the risk of breast cancer by disrupting some androgen signaling in the breast that may be protective for breast cancer (182)."
International Journal of ->-bleeped-<-, 13:165–232, 2011
"Progestins (especially medroxyprogesterone) are also suspected to increase breast cancer risk"
4) It has negative effects on the cardiovascular system whereas progesterone does not. It increases clotting risks. Whereas natural progesterone does not do this.
Climacteric. 2003 Dec;6(4):293-301
"Recent report, particularly the Women's Health
Initiative, demonstrated that hormone therapy with combined estrogen
plus progestin increased the incidence of heart attacks, stroke,
blood clots, breast cancer and dementia in women over 65 years old.
We investigated the role of synthetic progestins in initiating the
adverse events associated with estrogen therapy"
"The acute peripheral and cerebrovascular responses were measured following intraperitoneal
(...) or intravenous (...) administration of
progesterone, synthetic progestins (medroxyprogesterone acetate and
norethindrone) or estrogens (conjugated equine estrogens and 17 beta-
estradiol). "
"In both peripheral and cerebral vasculature,
synthetic progestins caused endothelial disruption, accumulation of
monocytes in the vessel wall, platelet activation and clot
formation, which are early events in atherosclerosis, inflammation
and thrombosis. Natural progesterone or estrogens did not show such
toxicity."
Maturitas. 2011 Dec;70(4):354-60.
"With respect to the different pharmacological classes of progestogens, there is evidence for a deleterious effect of medroxyprogesterone acetate on VTE risk. In addition, observational studies showed that norpregnane derivatives were significantly associated with an increased VTE risk whereas micronized progesterone could be safe with respect to thrombotic risk."
CLINICAL THERAPEUTIC VOL. 21, NO. 1, 1999
Oral Micronized Progesterone
"the most commonly used synthetic progestins, norethisterone and medroxyprogesterone acetate, have been associated with metabolic and vascular side effects (eg, suppression of the vasodilating effect of estrogens) in both experimental and human controlled studies. All comparative studies to date conclude that the side effects of synthetic progestins can be minimized or eliminated through the use of natural progesterone, which is identical to the steroid produced by the corpus luteum."
"The progestins do, however, have a number of potential negative effects, particularly metabolic and vascular effects.12-18"
"all randomized, controlled studies in animals and humans have consistently shown that the most popular synthetic progestins, including those with only weak androgenic activity (eg, medroxyprogesterone acetate [MPAJ), induce significant disturbances in lipid levels, glucose metabolism, vasomotility, and histologic appearance of the artery walls. 12-18"
"In controlled animal studies and short-term human trials, however, no side effects were observed when circulating levels of natural progesterone were kept within the range seen during the normal luteal phase.14,18,20-22. Therefore, natural progesterone may have a better risk-benefit profile than that of the synthetic progestins."
"The results of published clinical studies show minimal or no changes in lipid profile, blood pressure, or carbohydrate metabolism during treatment with oral micronized progesterone.28 This safety profile contrasts with the reported negative effects of some synthetic progestins, including adverse effects on lipid metabolism and glucose tolerance. Several studies, including the 3-year prospective PEP1 study, 4, 28 have shown that oral micronized progesterone significantly improves metabolic tolerance compared with such progestins as MPA.52,54,58"
"Only minor adverse events have been reported in association with oral micronized progesterone therapy in clinical trials. Dizziness and sleepiness are the primary adverse reactions reported.33 However, these side effects can be suppressed by administering micronized progesterone once daily at bedtime. 29 Oral micronized progesterone is therefore an effective and well-tolerated form of progestogen replacement in premenopausal and postmenopausal women"
Experimental and Clinical Psychopharmacology Copyright 2007 by the American Psychological Association
2007, Vol. 15, No. 5, 427–444
"It is important to note that although progesterone and synthetic progestins are used for similar purposes, these may not exert similar modulatory effects on target organs, and each progestin molecule may have specific effects on neuroendocrine action (Bernardi et al., 2006). For example, a commonly used progestin, MPA, was shown to induce more negative somatic effects (...) in comparison with natural (micronized, oil-suspended) progesterone in early menopausal women (Cummings & Brizendine, 2002). MPA and natural progesterone also were found to differ with respect to molecular signaling in human endothelial cells, suggesting that there may be differential cardiovascular effects (Simoncini et al., 2004)."
Biol Psychol. 2005 Apr;69(1):39-56. Epub 2005 Jan 4.
"Women assigned to Estratab plus Prometrium had diminished diastolic blood pressure responses during a speech stressor upon retesting, whereas women assigned to Estratab plus Provera increased."
Climacteric. 2013 Aug;16 Suppl 1:69-78.
"MPA transactivates both AR and GR, leading to related
side-effects and therefore cannot be compared with natural
progesterone 16 . »
"MPA – the most prescribed progestin in
the USA for HRT and also used in the WHI – transactivates
both the AR and the GR and exerts androgenic and glucocorticoid
activities, therefore differing considerably from
natural progesterone 1,16 . »
"MPA has been shown to potentiate the vascular procoagulant
effects of thrombin, an effect related to its glucocorticoid
action 1,66 . »
« In experiments conducted in ovariectomized female monkeys
fed a highly atherogenic diet, estrogens preserved normal
endothelial-dependent dilator responses of coronary arteries
to acetylcholine, and progesterone did not alter this
cardioprotective mechanism. While MPA diminished the
endothelium-dependent vasodilation 68 , »
"Estradiol has been shown to trigger the expression of the
endothelial nitric oxide synthase (eNOS) gene and increase the
release of nitric oxide, causing relaxation of the vascular
smooth muscle cells. »
"Progesterone or drospirenone did not interfere with the induction or activation
of eNOS by estradiol, while MPA did."
Natural Progesterone: What Role in Women's Health Care?
Whether it's right for your patient depends on the specific setting
JANE L. MURRAY, MD
"Estrogen/Progestin Interventions trial, high-density lipoprotein levels increased 3.5 times more in the group using micronized progesterone than in those receiving medroxyprogesterone acetate. Micronized progesterone appears to achieve this effect without producing any adverse effects on hemostasis, blood pressure, or levels of other lipids, probably because it has virtually no androgenic side effects."
"Natural progesterone appears to be an effective component of postmenopausal HRT and is preferable to standard progestational agents for women with worrisome lipid profiles or hypertension. Natural progesterone has fewer side effects than synthetic agents have"
Experimental and Clinical Psychopharmacology
2007, Vol. 15, No. 5, 427–444
Progesterone: Review of Safety for Clinical Studies
"Synthetic progestins marketed as Provera, PremPro, and Cycrin are widely used but may produce a number of significant side effects, such as (...) lipid level alterations, dysphoria, hypercoagulant states (...). Natural progesterones are reported to have milder adverse effects."
Steroids. 2003 Nov;68(10-13):831-6.
"Particularly, the Postmenopausal Estrogen/Progestin Intervention (PEPI) trial clearly showed the different impact of sequential micronized progesterone or medroxyprogesterone acetate (MPA) on estrogen therapy
(ET) with CEE. Indeed, while all women had increases in HDL-C and reductions in LDL-C while on estrogens, the addition of MPA was associated with a partial reversal of the positive effect on HDL-C (not on LDL-C), that was not obtained with micronized progesterone [5]."
"Indeed, by using Cynomolgus monkeys, Adams' group in North Carolina has been able to show consistently that 17β-estradiol modulates coronary arteries dilatation in estrogen-deprived animals [17]. Co-administration of natural progesterone did not alter the effect of estrogen. However, in the same model, the addition of cyclic or continuous MPA inhibited the vasodilatory effect of estrogen responses by 50% [18]. These data have been confirmed by other groups, showing that progesterone plus estradiol protects, but MPA plus estradiol does not, against coronary artery vasospasm[19], thus highlighting the difference between natural progesterone and MPA."
"As for the effects of progestins on vascular tone, the data are more limited, but some inferences can be drawn from the available data. Recent work looking at the additional effects of natural progesterone or MPA on coronary blood flow and myocardial ischemia in postmenopausal women shows that progesterone has synergistic vasodilatory effects when added to estrogens [26]. In contrast, MPA does not share this action, therefore indicating that, on this particular target, all progestins are not the same [26]."
J Am Coll Cardiol. 2000 Dec;36(7):2154-9.
"Combination estrogen/transvaginal progesterone gel increases exercise time to myocardial ischemia, as compared with estrogen/MPA. These results imply that the choice of progestin in women at higher cardiovascular risk requires careful consideration. »
Biochem Pharmacol. 2013 Dec 15;86(12):1627-42.
"Also, WHI showed an overall doubling of VTE events with MHT in the CEE + MPA arm [14], although the effect of MHT on VTE events was not significant in the CEE-alone arm (Table 1)."
Menopause. 2014 Jan 6.
"With regard to diabetes mellitus, which is a major risk factor
for CVD, CEE and transdermal estradiol seemed to have had
minimal effects on glucose metabolism and insulin resistance,
whereas MPA might have had a slightly adverse effect and MP
had no adverse effect.42 The PEPI Trial showed that CEE/MP,
unlike CEE/MPA, did not adversely affect carbohydrate metabolism.
11 »
MP = micronized progesterone
Drugs Aging 2004; 21 (13): 865-883
"In monkeys, neither natural progesterone nor nomegestrol acetate inhibits the beneficial effect of estrogen on the coronary artery dilator response. However, when medroxyprogesterone acetate was combined with estrogen, the positive response was inhibited by 50%.[69,70]"
Climacteric, 8 (Suppl. 1) (2005), pp. 3–63
"It was, however, demonstrated
that MPA exerts considerable glucocorticoid
effects mediated by binding to the glucocorticoid
receptor, which causes an upregulation of the
thrombin receptor and stimulates the procoagulatory
activity236. »
Fertil Steril. 2014 Apr;101(4):898-904.
"Prempro has been associated with numerous side effects, including heart disease, adverse changes in lipid metabolism, and thrombo-embolic processes (59). By contrast, micronized progestin (MP), bioidentical to the progesterone produced in the ovaries, has not been associated with such side effects. Taken together, evidence suggests that the type of hormone preparation utilized may significantly influence outcomes."
Maturitas 46S1 (2003) S7–S16
Classification and pharmacology of progestins
"unlike progesterone and dienogest, it was found that MPA, norethindrone acetate, and levonorgestrel increase expression of two markers of vascular inflammation, intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)"
"MPA was shown to have no effect on NO production in isolated human endothelial cells as well as in
aortas from ovariectomized rats, unlike progesterone and drospirenone, which increased NO production"
"MPA has been shown to display glucocorticoid-like negative effects on bone density"
"Similarly, GR-mediated transactivation is implicated in cardiovascular side effects for MPA and gestodene, which, unlike norethindrone and levonorgestrel, up-regulate proteolytically activatable thrombin receptor (PAR-1)mRNAin rat vascular smooth muscle primary cells to potentiate the vascular procoagulant effects of thrombin (193). Relevant to possible beneficial effects on cardiovascular function, MPA acting most likely via the GR down-regulates endothelial nitric oxide synthase (eNOS) mRNA expression and resulting nitric oxide levels in human umbilical vein endothelial cells"
Nat Med. 1997 Mar;3(3):324-7.
"Cardiovascular disease, the major cause of death in post-menopausal women, can be reduced by replacement of ovarian steroid hormones. To compare medroxyprogesterone with progesterone as the progestin in hormone replacement therapy from the standpoint of coronary artery vasospasm, we treated ovariectomized rhesus monkeys with physiological levels of estradiol-17 beta in combination with medroxyprogesterone or progesterone for four weeks. Coronary vasospasm in response to pathophysiological stimulation without injury showed that progesterone plus estradiol protected but medroxyprogesterone plus estradiol failed to protect, allowing vasospasm. We conclude that medroxyprogesterone in contrast to progesterone increases the risk of coronary vasospasm."
J Clin Endocrinol Metab. 1998 Feb;83(2):649-59.
"Ovx monkey VMC responses were hyperreactive, showing prolonged increases in intracellular Ca2+ and protein kinase C that correlated with exaggerated in vivo coronary artery vasoconstrictor responses. The hyperreactive Ca2+ responses were abolished by in vivo treatment with E2 and/or P. However, VMC from ovx monkeys treated with the combination of E2 and MPA or E2, P, and MPA remained hyperreactive to vasoconstrictor stimuli, suggesting that MPA negated the protective effects of E2."
International Journal of ->-bleeped-<-, 13:165–232, 2011
"Progestins (especially medroxyprogesterone) are also suspected to increase (...) cardiovascular risk in women (Rossouw et al., 2002). Micronized progesterone may be better tolerated and have a more favorable impact on the lipid profile than medroxyprogesterone does (de Lignieres, 1999; Fitzpatrick, Pace, & Wiita, 2000)."
And 5) finally, this is somewhat worrisome...
AJNR Am J Neuroradiol. 2010 Sep;31( 8 ):1504-5.
"the growth of multiple meningiomas was observed during a 4-year period after administration of medroxyprogesterone acetate, followed by a spontaneous regression after hormonal withdrawal.11"
