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Progesterone

Common Name(s): Hormonil, Micronized progesterone, MyGest, Natural progesterone, Phytoprolief, Pro-Gest, Progesta-Eze, Progestelle, Progesterone cream, Prov-Juven, Women to Women Body Cream, Young Again Natural Progesterone Cream

Clinical Overview

Use

Topical progesterone is used to manage menopause-related symptoms, such as hot flashes, low libido, and mood swings. Clear evidence of a progesterone benefit in improving bone density or cardiovascular markers, or for the prevention of endometrial proliferation, is lacking. Topical progesterone has also been studied for the management of cyclic breast pain and for skin elasticity and firmness in postmenopausal women.

Dosing

Most trials evaluated topical progesterone 40 mg daily either as a single dose or 20 mg twice daily for menopausal symptoms.

Contraindications

None documented.

Pregnancy/Lactation

Information regarding topically applied progesterone in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Clinical trials report few adverse events, with most no different from those of the placebo comparator. A higher incidence of headache and postmenopausal bleeding has been reported.

Toxicology

Research reveals no information regarding the toxicity of topical progesterone.

Source

Phytoestrogens, structurally similar to human estrogen and progesterone, are synthesized by more than 5,000 plants. Progesterone can be converted from the sterol diosgenin found in plants such as soybeans and wild yam.1 This monograph is limited to evidence for progesterone cream and does not include references to wild yam or soy. (See Wild Yam or Soy monographs for more information.) Despite claims that natural progesterone is plant-based and therefore from a natural source, many synthesized progesterones are also plant-derived and are chemically identical to progesterone of the ovarian origin.2

History

"Natural" progesterone cream has been available in the United States for at least 20 years as an over-the-counter preparation and is not regulated by the FDA.1, 3, 4 Transdermal delivery was proposed as an alternative to the oral route because approximately 90% of progesterone is enzymatically inactivated in the gut and liver, and results in undesirable metabolites are produced.1

Claims for the use of topical natural progesterone include the prevention and treatment of osteoporosis and low libido, as well as the management of menopausal symptoms, including hot flashes, and enhancement of mood and psychological well being.1, 3

Chemistry

Progesterone, a principle of corpus luteum, is the primary endogenous progestational substance. Progestins (progesterone and derivatives) transform proliferative endometrium into secretory endometrium. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo.5

Progesterone receptors have been identified in whole skin, keratinocytes, and fibroblasts.1

Micronized progesterone is used in oral and topical preparations to enhance absorption.2

Uses and Pharmacology

Clinical studies have been conducted to describe the pharmacokinetics of topical progesterone, with most studies finding major increases in salivary progesterone and only moderate increases in serum progesterone levels. Wide variations in measured progesterone levels are also a feature of these studies.1, 6, 7, 8, 9, 10 In a crossover study, topical progesterone 40 mg twice daily showed no difference compared with oral progesterone 200 mg in the 24-hour area under the curve (AUC) for whole blood progesterone3 while another kinetic study using a daily progesterone 60 mg cream achieved serum progesterone levels similar to luteal levels (more than 3 ng/mL).11 A clinical trial evaluating the effect of progesterone on bone density found increases in serum progesterone for up to 6 months with no further accumulation. At 3 years, the mean serum progesterone level was 3.54 nmol/L.12

Various mechanisms have been proposed to explain the observed low plasma levels of progesterone following topical application. These include uptake by the red blood cells, rapid conversion to 5-alpha-reduced progestin, and rapid clearance from the serum by salivary and hepatic excretion, combined with slow transdermal absorption.1, 7, 9 A "priming" effect of the skin resulting in increased absorption after a few days of administration has also been suggested.7, 13

Genital lichen sclerosus

A systematic review and meta-analysis of randomized controlled trials that investigated use of topical interventions for genital lichen sclerosus found no evidence to support the use of topical progesterone as a treatment option. Of the 7 studies that met inclusion criteria, only 1 evaluated topical progesterone (2% cream) and found no significant difference compared to placebo after 3 months application.50

Menopause/Menopausal symptoms

Animal data

Studies in animals are limited. In a study conducted in rats, topical progesterone was found to be effectively and biologically actively absorbed. A similar distribution in tissues was found following intramuscular administration. Metabolism was also similar.14

Clinical data

Debate exists about the relevance of plasma and salivary progesterone as surrogate indicators of clinical efficacy.1, 8, 9, 15 Clear evidence of a progesterone benefit in improving bone density or cardiovascular markers, or for the prevention of endometrial proliferation is lacking.6, 16, 17, 18, 19

In an open-label study, topical progesterone 40 mg daily applied for over 1 year did not provide adequate opposition to endometrial hyperplasia as determined by endometrial histology and bleeding patterns in 41 postmenopausal women.20, 21 A small clinical crossover trial (N = 26) found topical progesterone 40 mg daily to exert a similar effect on the endometrium as standard oral progesterone.22 In a large (N = 223), double-blind, randomized trial, topical progesterone (Progestelle) applied for over 6 months showed no difference compared with placebo for psychological, somatic, or vasomotor menopause-related symptoms. Dosages of progesterone 5, 20, 40, and 60 mg daily were tested. A string placebo effect was observed. No histological effect of topical progesterone on the endometrium was demonstrated.23 In a randomized clinical study, results with topical progesterone 32 mg did not differ from those with placebo for vasomotor symptoms, mood, or libido, and showed no effect on blood lipids or bone metabolic markers.10

In a randomized clinical trial (N = 102), topical progesterone 20 mg daily showed no protective effect on bone density at 1 year and no change in the lipid profile versus placebo. However, an improvement in vasomotor symptoms was recorded.24 A 2-year study evaluating the effect of soy and transdermal progesterone on bone mineral density in postmenopausal women found progesterone alone to have protective effects on the lumbar spine but not hip bone, but the positive effect was attenuated when used in combination with soy milk.25 No effect on bone density or plasma lipids was found for topical progesterone 40 mg daily in a large, double-blind, randomized clinical trial (N = 131 postmenopausal women).12

Other uses

Topical progesterone was no better than placebo for the management of cyclic breast pain in a small clinical trial.26 A progesterone 2% cream increased the elasticity and firmness of skin in postmenopausal women in a small study.13

Dosing

Commercial progesterone creams vary in concentration but are generally in the range of 1.5% to 3% progesterone. Most trials evaluated progesterone 40 mg daily either as a single dose or 20 mg twice daily for menopausal symptoms.12, 20, 21

Pregnancy / Lactation

Information regarding topically applied progesterone in pregnancy and lactation is lacking.

Interactions

Anticoagulants: Progestins may diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. The use of an estrogen derivative may modify the thromboembolic risk associated with this combination. Numerous comorbid states and other patient characteristics may modify the thromboembolic risk associated with this combination. Recommendations for management of this interaction may differ depending on the indication for progestin treatment (eg, for hormone replacement therapy vs. contraception). Consider therapy modification.51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68

Antidiabetic agents: Hyperglycemia-associated agents may diminish the therapeutic effect of antidiabetic agents. Monitor therapy.69, 70, 71, 72, 73, 74, 75, 76

Antifungal agents (vaginal): Antifungal agents (vaginal) may diminish the therapeutic effect of progesterone. This interaction only applies to the vaginal progesterone product (Endometrin) and vaginal antifungal products. Avoid combination.77, 78

Bosentan: Bosentan may decrease the serum concentration of CYP3A4 substrates. Monitor therapy.79, 80

C1 inhibitors: Progestins may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy.81, 82, 83, 84, 85

Cyclosporine (systemic): Progestins may enhance the hepatotoxic effect of cyclosporine(systemic). Progestins may increase the serum concentration of cyclosporine (systemic). Monitor therapy.30, 31

CYP2C19 inducers (strong): CYP2C19 inducers (strong) may increase the metabolism of CYP2C19 substrates. Consider therapy modification.32, 33

CYP3A4 inducers (moderate): CYP3A4 inducers (moderate) may decrease the serum concentration of CYP3A4 substrates (high risk with inducers). Monitor therapy.86, 87

CYP3A4 inducers (strong): CYP3A4 inducers (strong) may increase the metabolism of CYP3A4 substrates. Consider therapy modification.32, 33

Deferasirox: Deferasirox may decrease the serum concentration of CYP3A4 substrates. Monitor therapy.34

Enzalutamide: Enzalutamide may decrease the serum concentration of CYP3A4 substrates (high risk with inducers). Consider therapy modification.88, 89

Herbs (progestogenic properties): Herbs (progestogenic properties) may enhance the adverse/toxic effect of progestins. Monitor therapy.35

Ivosidenib: Ivosidenib may decrease the serum concentration of CYP3A4 substrates (high risk with inducers). Monitor therapy.90

Lomitapide: CYP3A4 inhibitors (weak) may increase the serum concentration of lomitapide. Consider therapy modification.36

Mitotane: Mitotane may decrease the serum concentration of CYP3A4 substrates (high risk with inducers). Consider therapy modification.91, 92, 93, 94, 95, 96, 97

Pitolisant: Pitolisant may decrease the serum concentration of CYP3A4 substrates (high risk with inducers). Consider therapy modification.98, 99

Pomalidomide: Progestins may enhance the thrombogenic effect of pomalidomide. Canadian labeling specifically recommends avoiding use of hormonal contraceptives and recommends caution with use of hormone replacement therapy. US labeling does not contain these specific warnings. Consider therapy modification.37

Sarilumab: Sarilumab may decrease the serum concentration of CYP3A4 substrates (high risk with inducers). Monitor therapy.100, 107, 108

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of silodosin. Avoid combination.38

Siltuximab: Siltuximab may decrease the serum concentration of CYP3A4 substrates (high risk with inducers). Monitor therapy.100, 101

St. John’s wort: St John's wort may decrease the serum concentration of CYP3A4 substrates (high risk with inducers). Consider therapy modification.33, 86, 102, 103, 104

Tocilizumab: Tocilizumab may decrease the serum concentration of CYP3A4 substrates (high risk with inducers). Monitor therapy.39, 40, 41

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of topotecan. Avoid combination.42, 43, 44, 45, 46, 47, 48, 49

Ulipristal: Progestins may diminish the therapeutic effect of ulipristal. Ulipristal may diminish the therapeutic effect of progestins. Avoid combination.105, 106

Adverse Reactions

Clinical trials report few adverse events, with most no different from those of the placebo comparator.11, 23 A higher incidence of headache and postmenopausal bleeding was associated with topical progesterone in 1 large clinical study.23 Water retention, breast engorgement, increased body weight, and mild to moderate depression have been documented in case reports following long-term use.27

While progesterone cream may be helpful for women with proven low progesterone levels, for women experiencing symptoms due to relative progesterone deficits, meaning more or less normal progesterone levels but with estrogen excess, progesterone cream may increase the hormonal load in the body. Aromatase enzymes in adipose cells below the dermis convert androgens, including progesterone, into estrogen. Therefore, women with hyperestrogenism may not benefit and may even be harmed by progesterone supplementation if it is not prescribed appropriately.28, 29

Toxicology

Research reveals no information regarding the toxicity of topical progesterone.

References

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This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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