Progesterone vs Synthetic Progestins: Clinical Options
James A. Simon, MD, Clinical Professor, George Washington University, Washington, DC, notes: “Clinicians have numerous options in selecting a progestogen for the individual patient. The specific properties of progesterone or synthetic progestins may result in differing side-effect profiles for individual patients. Route of administration also offers differing systemic or local effects that should be considered for some uses and specific patients.” Differences exist among the exogenous progestogens, which include both natural progesterone and synthetic and semi-synthetic progestins, drugs which are “structurally related - but are not identical - to either progesterone or testosterone... Progesterone and progestins differ not only in their structure, but also in their potency, as determined by standard bioassays... Additionally, studies often do not evaluate the effects of progestogens on specific organs or compare the side-effect profiles of individual agents. These characteristics constitute an important, although rarely discussed, aspect of the differences among progestogens.”
The Journal of Family Practice 2007 Feb; 2(7):S3-S5
Comparison of Different Routes of Progesterone Administration for Luteal Phase Support in Infertility Treatment
Different routes of natural progesterone supplementation have been tried as luteal phase support in infertility treatments. Orally administered progesterone is rapidly metabolized in the gastrointestinal tract and oral administration has proven to be inferior to intramuscular (IM) and vaginal routes. Progesterone IM achieves serum progesterone values that are within the range of luteal phase and results in sufficient secretory transformation of the endometrium and satisfactory pregnancy rates. The comparison between IM and vaginal progesterone has led to controversial results as regards the superiority of one or the other in inducing secretory endometrial transformation. However, there is increasing evidence in the literature to favor the use of vaginal progesterone. Vaginally administered progesterone achieves adequate endometrial secretory transformation but its pharmacokinetic properties are greatly dependent on the formulation used. After vaginal progesterone application, discrepancies have been detected between serum progesterone values and histological endometrial features. Vaginally administered progesterone results in adequate secretory endometrial transformation, despite serum progesterone values lower than those observed after IM administration, even if they are lower than those observed during the luteal phase of the natural cycle. This discrepancy is indicative of the first uterine pass effect and therefore of a better bioavailability of progesterone in the uterus, with minimal systematic undesirable effects.
Hum Reprod Update. 2000 Mar-Apr;6(2):139-48.
Comparison between different routes of progesterone administration as luteal phase support in infertility treatments.
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Uses of Progesterone in Clinical Practice
Progesterone is the natural progestogen produced by the corpus luteum during the luteal phase. It is absorbed when administered orally, but is greater than 90% metabolized during the first hepatic pass. This greatly limits the efficacy of once-daily administration and also results in “unphysiologically” high levels of progesterone metabolites which can cause dizziness and drowsiness to the point of preventing the operation of a motor vehicle. Synthetic progestins, such as medroxyprogesterone acetate and norethindrone acetate, have been specifically designed to resist enzymatic degradation and remain active after oral administration. However, according to Drs. Warren and Shantha of the Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, these synthetic progestins exert undesirable effects on the liver and often cause severe psychological side effects. Transvaginal administration of progesterone is a practical non-oral route available for administering progesterone. Early experience was gained with vaginal suppositories. The clinical acceptance of progesterone administered as a vaginal gel was enhanced by the characteristics of a polycarbophil-based gel, which conveys controlled and sustained-released properties. Investigations have shown that because of local direct vagina-to-uterus transport, which results in a preferential uterine uptake of progesterone, progesterone vaginal gel given in conjunction with physiological amounts of estradiol produces endometrial changes similar to those seen in the luteal phase, despite plasma progesterone levels that remain subphysiologic. Studies in infertility show that vaginal progesterone in this form allows secretory transformation of the endometrium and the development of pregnancy despite providing low systemic progesterone concentrations. Fewer side effects occur when vaginal progesterone is used for hormone replacement than are typically encountered with progestins and oral progesterone.
Int J Fertil Womens Med. 1999 Mar-Apr;44(2):96-103
Uses of progesterone in clinical practice.
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Pregnenolone – The Parent Hormone Affecting Memory, Sleep, Anxiety, and Mood
• Pregnenolone is at the top of the hormone cascade, the “parent hormone” from which neurosteroids and sex hormones are formed, and gives rise to important “neurohormones” that affect learning, memory, mood, sleep, and many other functions.
• Pregnenolone may relieve anxiety, help to fight depression, and reduce symptoms of withdrawal from nicotine and alcohol addiction.
• Hormone levels naturally decline with advancing age. People with lower pregnenolone levels are more likely to suffer from memory deficits, mood disorders, and even some mental illnesses.
• Pregnenolone and other neuroactive steroids can protect brain cells against the long-term damage that can lead to Alzheimer’s disease and other forms of dementia.
The conversion of cholesterol to pregnenolone constitutes the first of many steps in the synthesis of some of the body’s key hormones, including dehydroepiandrosterone (DHEA), testosterone, progesterone, estrogen, and cortisol. Pregnenolone’s metabolites fulfill a myriad of essential roles in the body, from stimulating memory via excitatory pathways to easing anxiety through inhibitory mechanisms.1,2
Pregnenolone has vast potential for maintaining healthy cognitive function and may be “the most potent memory enhancer yet reported.”3 Alzheimer’s disease patients have lower levels of pregnenolone, allopregnanolone (a pregnenolone metabolite) and DHEA-sulfate (DHEAS) in all the main memory-related areas of their brains, compared with control patients. Furthermore, the brains of patients with the highest neurosteroid levels display the lowest collections of the destructive amyloid-beta proteins. 4,5,6
Researchers have also shown that pregnenolone increases brain levels of acetylcholine, a key neurotransmitter required for optimal brain function, which is deficient in patients with Alzheimer’s disease. 7 Acetylcholine is not only vital for thought and memory, it is also involved in controlling sleep cycles, especially the phase of sleep that is associated with memory (called paradoxical sleep or the random eye movement [REM] phase).
Neurosteroids are known to affect anxiety in humans.8 Researchers from the University of California in San Francisco performed two studies of pregnenolone and anti-anxiety medications and concluded that pregnenolone, taken as a supplement while using an anti-anxiety medication, could reduce many adverse effects of the medication, such as sedation and memory impairment. 9
There is increasing evidence that lower levels of pregnenolone are associated with a variety of mental health conditions beyond anxiety, including depression, phobias, and even schizophrenia.10,11,12,13 One study revealed that schizophrenic patients with the lowest levels of pregnenolone were also most likely to have high levels of anxiety.14
Pregnenolone and other neurosteroids have also been shown to counteract the anxiety-like behavior that is associated with nicotine or morphine withdrawal, due to their potent effects on sigma receptors, and may offer relief to individuals seeking to overcome these addictions. 15,16
Please click on the links below for more information.
http://www.lef.org/magazine/mag2007/nov2007_report_pregnenolone_01.htm
1 Pharmacol Biochem Behav. 2006 Aug;84(4):555-67.
2 Jpn J Pharmacol. 1999 Oct;81(2):125-55.
3 Proc Natl Acad Sci USA. 1995 Nov 7;92(23):10806-10.
4 Prog Neurobiol. 2003 Sep;71(1):3-29.
5 J Clin Endocrinol Metab. 2002 Nov;87(11):5138-43.
6 Biol Psychiatry. 2006 Dec 15;60(12):1287-94.
7 Prog Neurobiol. 2003 Sep;71(1):43-8.
8 Neuropsychobiology. 2004;50(1):6-9.
9 Psychoneuroendocrinology. 2004 May;29(4):486-500.
10 Prog Neuropsychopharmacol Biol Psychiatry. 2005 Feb;29(2):169-92.
11 Neuropsychopharmacology. 2005 Jun;30(6):1181-6.
12 Pharmacol Biochem Behav. 2006 Aug;84(4):644-55.
13 Am J Psychiatry. 2002 Jan;159(1):145-7.
14 Eur Neuropsychopharmacol. 2007 Apr;17(5):358-65.
15 J Pharmacol Sci. 2006 Feb;100(2):93-118.
16 Brain Res Brain Res Rev. 2001 Nov;37(1-3):116-32.
Researchers at The University of Texas at Tyler, led by Kenna Stephenson, M.D., showed that use of progesterone in a topical cream (20 mg per day) relieved menopausal symptoms. In addition, in a subpopulation of hypercortisolemic women, nocturnal cortisol levels were reduced to normal range while they were using the progesterone cream as compared to placebo. Stress activates cortisol, and an abnormal cortisol pattern has been associated with an increased risk of heart attacks, cancer, obesity and other diseases.
Blood 2004 Nov; 104(11):16
Progesterone Relieves Menopausal Symptoms and Normalizes Nocturnal Cortisol Levels
The French E3N-EPIC cohort study assessed the risk of breast cancer associated with HRT use in 54,548 postmenopausal women.
Breast Cancer Res Treat. 2008 Jan;107(1):103-11
Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study.
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The neuroprotective and promyelinating effects of progesterone are promising not only for preventing, but also for reversing, age-dependent changes and dysfunctions.
Endocr Rev. 2007 Jun;28(4):387-439.
Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system.
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linical evidence shows that, during menopause, estrogen withdrawal gives rise to modifications in mood, behavior and cognition and that estrogen administration is able to improve mood and cognitive efficiency in post-menopause. There may be a critical period of time for HRT-related neuroprotection, and early initiation of estrogen therapy may be necessary for cognitive benefit.
Hum Reprod Update. 2007 Mar-Apr;13(2):175-87
Estrogen, cognition and female ageing.
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J Clin Endocrinol Metab. 2006 Jan;91(1):136-44.
Pharmacokinetics of Testosterone Gel in Healthy Postmenopausal Women
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Absorption and Efficacy of Multiple Hormones Delivered in a Single Cream
This study is the first documenting systemic absorption of multiple hormones by both saliva and blood as well as improvement of health-related quality of life.
Gynecol Obstet Invest. 2008 Apr 29;66(2):111-118.
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New research from the Women's Health Initiative Memory Study (WHIMS) links the use of hormone replacement therapy (HRT) before the age of 65 years to a reduced risk of all-cause dementia and Alzheimer's disease (AD) in women. At the American Academy of Neurology’s 59th Annual Meeting, researchers presented an analysis that showed early HRT use was associated with a 46% overall reduction in dementia risk and a 64% reduction in AD. WHIMS also included 2 studies that looked at cognitive outcomes and HRT in women over 65 years old. At an average 5-year follow-up, both the conjugated equine estrogens plus medroxyprogesterone acetate (CEE + MPA) and the CEE-alone trials showed conjugated estrogens, with or without MPA, increased dementia risk when therapy was initiated after age 65 years. In the CEE + MPA trial the risk doubled, while in the CEE-alone trial there was about a 50% increased risk. There is evidence from animal models suggesting estrogen at an earlier age may be beneficial, and these results are intriguing because they seem to support that evidence.
While studies describe the therapies used in the WHI as “estrogen with or without progesterone”, the WHI actually used only synthetic CEE and MPA (which is chemically different than progesterone).
HRT Before Age 65 May Decrease Risk of Dementia and Alzheimer’s Disease
American Academy of Neurology 59th Annual Meeting: Abstract S31.004. April 28 – May 5, 2007
Click here to access the Medscape article. (accessed April 4, 2008)
Progesterone Therapy for Catamenial Epilepsy
Catamenial epilepsy refers to seizures that occur or worsen around menstruation. Researchers at North Carolina State University evaluated the hypothesis that neurosteroid "replacement" is an effective and a rational therapy for catamenial epilepsy. It is well known that progesterone possesses anticonvulsant properties. The clustering of seizures around the beginning of menstruation corresponds with a significant drop in the levels of progesterone circulating in the body and an increase in the estrogen:progesterone ratio. Recent studies have shown that progesterone is metabolized to the neurosteroid allopregnanolone which plays a crucial role in seizure protection. Declining levels of allopregnanolone, which occur during the menstrual cycle, can provoke seizures.
“Cyclic natural progesterone use has been demonstrated as an effective treatment for catamenial and non-catamenial seizures in women. Progesterone is efficiently absorbed after oral administration as lozenges, and rectal administration as suppositories.” Progesterone was given at 100 to 200 mg, t.i.d. on days 15 to 28 of the menstrual cycle. In a 3 month investigation of cyclic natural progesterone therapy, 23 of 25 (92%) women continued on the same AED and progesterone protocol and continued to have a very substantial (62% to 74%) reduction in seizure frequency.
Epilepsy Behav. 2008 Mar 16 [Epub ahead of print]
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Seizure. 2008 Mar;17(2):176-80.
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Indian Journal of Pharmacology 2005; 37(5):288-293
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Neurology 1995;45:1660-2
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Neurology 1999;52:1917-8
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The Women's Health Initiative Memory Study (WHIMS) links the use of hormone replacement therapy (HRT) before the age of 65 years to a reduced risk of all-cause dementia and Alzheimer's disease (AD) in women.
American
Academy of Neurology 59th Annual Meeting: Abstract S31.004.
April 28 - May 5, 2007
Click here to read a Medscape article on this topic.
The following finding that conjugated equine estrogen was associated with venous thrombotic risk may have implications for the choice of hormones in perimenopausal and postmenopausal women.
JAMA. 2004 Oct 6;292(13):1581-7
Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis.
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These observations suggest that the addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk-thereby returning the incidence to the normal rates observed in the general, untreated population.
Menopause. 2004 Sep-Oct;11(5):531-5
Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy.
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The pharmacodynamic differences of testosterone and methyltestosterone are briefly reviewed in the context of choice for individualized clinical use.
Mayo Clin Proc. 2004 Apr;79(4 Suppl):S8-13
Hot flashes and androgens: a biological rationale for clinical practice.
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The results of this study suggest a significant reduction in the incidence of type 2 diabetes in our population of non-obese, healthy postmenopausal women who used transdermal 17-beta-estradiol. This could suggest that, in some women, the estrogen deficiency that occurs after menopause could represent a fundamental step in the process of diabetogenesis.
Diabetes Care. 2004 Mar;27(3):645-9
Transdermal 17-beta-estradiol and risk of developing type 2 diabetes in a population of healthy, nonobese postmenopausal women.
The full text article is available FREE online: http://care.diabetesjournals.org/cgi/content/full/27/3/645
Mayo Clinic researchers surveyed 176 women taking natural micronized progesterone who had previously taken synthetic progestins. After one to six months, the women reported an overall 34% increase in satisfaction on micronized progesterone compared to their previous HRT, reporting these improvements: 50% in hot flashes, 42% in depression, and 47% in anxiety. Micronized progesterone was also more effective in controlling breakthrough bleeding.
J Womens Health Gend Based Med 2000 May;9(4):381-7
Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey.
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Fertil Steril 1999 Sep;72(3):389-97
Micronized progesterone: clinical indications and comparison with current treatments.
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J Am Coll Cardiol 2000 Dec;36(7):2154-9
Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. (This is not a "claim", it is the title of the article.)
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An extensive federally sponsored double-blind study was conducted at 19 academic medical centers that comprise the Maternal-Fetal Medicine Units Network under the National Institutes of Health and found that 17-alpha-hydroxyprogesterone caproate (17P) provides substantial benefit for decreasing the risk of pre-term birth at less than 37 weeks gestation.
N Engl J Med 2003;348:2379-85
Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate.
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Am J Obstet Gynecol 2007;196:224.e1-224.e4.
Increased recurrence of preterm delivery with early cessation of 17-alpha-hydroxyprogesterone caproate.
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Vaginal progesterone suppositories have also been shown to decrease the rate of preterm birth in patients at increased risk. Da Fonseca et al noted that among 142 women who had one prior preterm birth, prophylactic cerclage, or uterine malformation, daily use of a 100-mg vaginal progesterone suppository compared with placebo significantly decreased the likelihood of delivery prior to 37 weeks.
Am J Obstet Gynecol. 2003; 188(2):419-424.
Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
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Other related articles:
Obstet Gynecol 2005 May;105(5 Pt 1):1128-35
Am J Obstet Gynecol. 2007 May;196(5):453.e1-4
The PEPI Trial, a 3-year multicenter, randomized, double-blind, placebo-controlled study of 875 healthy postmenopausal women, stated that synthetic progestins partially negate the beneficial effects on cholesterol levels that result from taking estrogen. Natural progesterone maintained the benefits of estrogen on cholesterol without side effects.
JAMA 1995 Jan 18;273(3):199-208
Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.
The Writing Group for the PEPI Trial.
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Certain progestogens, such as micronized progesterone, can be administered concurrently with estrogen replacement therapy, providing protection against endometrial hyperplasia without significantly affecting the beneficial effects of estrogen on lipid profiles, atherosclerosis and vascular reactivity.
J Reprod Med 2000 Mar;45(3 Suppl):245-58
Rationale for hormone replacement therapy in atherosclerosis prevention.
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J Clin Endocrinol Metab 2002;87:1062-1067
Estrogen status correlates with the calcium content of coronary atherosclerotic plaques in women.
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J Neurosci. 2003 Dec 10;23(36):11420-6
Estradiol attenuates programmed cell death after stroke-like injury.
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Endocrinology 2001 Mar 1;142(3):969-973
Minireview: Neuroprotective Effects of Estrogen-New Insights into Mechanisms of Action.
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The use of conjugated equine estrogen plus medroxyprogesterone acetate in a double-blind, randomized, controlled trial of 16,608 postmenopausal women between the ages of 50 and 79 years doubled the risk of venous thrombosis. This estrogen, which is derived from pregnant mares' urine, plus synthetic progestin therapy increased the risks associated with age, overweight or obesity, and factor V Leiden.
JAMA. 2004 Oct 6;292(13):1573-80
Estrogen plus progestin and risk of venous thrombosis.
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Chem Res Toxicol 1998 Sep;11(9):1105-11
The equine estrogen metabolite 4-hydroxyequilenin causes DNA single-strand breaks and oxidation of DNA bases in vitro.
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The following study concluded that in non-human primates, medroxyprogesterone increases the risk of coronary vasospasm. Progesterone plus estradiol protected against vasospasm.
Nat Med 1997 Mar;3(3):324-7
Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm.
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MPA reduces the dilatory effect of estrogens on coronary arteries, increases the progression of coronary artery atherosclerosis, accelerates low-density lipoprotein uptake in plaque, increases the thrombogenic potential of atherosclerotic plaques and promotes insulin resistance and its consequent hyperglycemia. These effects may be largely limited to MPA and not shared with other progestogens.
J Reprod Med 1999 Feb;44(2 Suppl):180-4
Progestogens and cardiovascular disease. A critical review.
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Significant bone loss occurs during the 10 to 15 years before menopause when estrogen levels are still normal. Progesterone can stimulate new bone formation in women with osteoporosis. Dr. Prior measured estrogen and progesterone levels in female marathon runners who had osteoporosis. Although their estrogen levels were still high, they had stopped ovulating (common in female athletes) and progesterone levels had fallen, triggering the onset of osteoporosis. This can indicate a role for progesterone use, alone or combined with estrogen which reduces bone loss, in improving Bone Mineral Density.
Endocr Rev 1990 May;11(2):386-98
Progesterone as a bone-trophic hormone.
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The WHI assessed the major health benefits and risks of the most commonly used combined hormone preparation in the United States, the synthetic combination of conjugated equine estrogens and medroxyprogesterone acetate. Absolute excess risks per 10,000 person-years attributable to this synthetic hormone combination were 7 more CHD events, 8 more strokes, 8 more pulmonary emboli, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures.
JAMA. 2002 Jul 17;288(3):321-33
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.
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Among postmenopausal women aged 65 years or older, synthetic estrogen plus progestin did not improve cognitive function when compared with placebo. However, typical HRT users are in their 50s and this study focused on women aged 65 and over, who have a higher risk for dementia.
JAMA 2003 May 28;289(20):2663-72
Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial.
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In the following study, estrogen plus progestin increased the risk of ischemic stroke in generally healthy postmenopausal women.
JAMA 2003 May 28;289(20):2673-84
Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial.
