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Progesterone

Systematic (IUPAC) name
pregn-4-ene-3,20-dione
Identifiers
CAS number	57-83-0
ATC code	G03DA04
PubChem	5994
DrugBank	APRD00700
Chemical data
Formula	C21H30O2
Mol. mass	314.46
Synonyms	4-pregnene-3,20-dione
Physical data
Melt. point	126 °C (259 °F)
Spec. rot	[α]D
Pharmacokinetic data
Bioavailability	prolonged absorption, half-life approx 25-50 hours
Protein binding	96%-99%
Metabolism	hepatic to pregnanediols and pregnanolones
Half life	34.8-55.13 hours
Excretion	renal
Therapeutic considerations
Pregnancy cat.	B (USA)
Legal status
Routes	oral, implant
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Progesterone also known as P4 (pregn-4-ene-3,20-dione) is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen.

Progesterone is commonly manufactured from the yam family, Dioscorea. Dioscorea produces large amounts of a steroid called diosgenin, which can be converted into progesterone in the laboratory.

Chemistry

Progesterone was independently discovered by four research groups.^[1][2][3][4]

Willard Myron Allen co-discovered progesterone with his anatomy professor George Washington Corner at the University of Rochester Medical School in 1933. Allen first determined its melting point, molecular weight, and partial molecular structure. He also gave it the name Progesterone derived from Progestational Steroidal ketone.^[5]

Like other steroids, progesterone consists of four interconnected cyclic hydrocarbons. Progesterone contains ketone and oxygenated functional groups, as well as two methyl branches. Like all steroid hormones, it is hydrophobic.

Sources

Animal

Progesterone is produced in the ovaries (specifically after ovulation in the corpus luteum), the adrenal glands (near the kidney), and, during pregnancy, in the placenta. Progesterone is also stored in adipose (fat) tissue.

In humans, increasing amounts of progesterone are produced during pregnancy:

• Initially, the source is the corpus luteum that has been "rescued" by the presence of human chorionic gonadotropins (hCG) from the conceptus.

• However, after the 8th week production of progesterone shifts to the placenta. The placenta utilizes maternal cholesterol as the initial substrate, and most of the produced progesterone enters the maternal circulation, but some is picked up by the fetal circulation and used as substrate for fetal corticosteroids. At term the placenta produces about 250 mg progesterone per day.

• An additional source of progesterone is milk products. They contain much progesterone because on dairy farms cows are milked during pregnancy, when the progesterone content of the milk is high. After consumption of milk products the level of bioavailable progesterone goes up.^[6]

Plants

In at least one plant, Juglans regia, progesterone has been detected.^[7] In addition, progesterone-like steroids are found in Dioscorea mexicana. Dioscorea mexicana is a plant that is part of the yam family native to Mexico.^[8] It contains a steroid called diosgenin that is taken from the plant and is converted into progesterone.^[9] Diosgenin and progesterone are found in other Dioscorea species as well.

Another plant that contains substances readily convertible to progesterone is Dioscorea pseudojaponica native to Taiwan. Research has shown that the Taiwanese yam contains saponins — steroids that can be converted to diosgenin and thence to progesterone.^[10]

Many other Dioscorea species of the yam family contain steroidal substances from which progesterone can be produced. Among the more notable of these are Dioscorea villosa and Dioscorea polygonoides. One study showed that the Dioscorea villosa contains 3.5% diosgenin.^[11] Dioscorea polygonoides has been found to contain 2.64% diosgenin as shown by gas chromatography-mass spectrometry.^[12] Many of the Dioscorea species that originate from the yam family grow in countries that have tropical and subtropical climates.^[13]

Synthesis

Biosynthesis

Top: Conversion of cholesterol (1) into pregnenolone (3) to progesterone (6).
Bottom: Progesterone is important for aldosterone (mineralocorticoid) synthesis, as 17-hydroxyprogesterone is for cortisol (glucocorticoid), and androstenedione for sex steroids.

In mammals, progesterone (6), like all other steroid hormones, is synthesized from pregnenolone (3), which in turn is derived from cholesterol (1) (see the upper half of the figure to the right).

Cholesterol (1) undergoes double oxidation to produce 20,22-dihydroxycholesterol (2). This vicinal diol is then further oxidized with loss of the side chain starting at position C-22 to produce pregnenolone (3). Biologically, this reaction is catalyzed by cytochrome P450scc. The conversion of pregnenolone to progesterone takes place in two steps. First, the 3-hydroxyl group is oxidized to a keto group (4) and second, the double bond is moved to C-4, from C-5 through a keto/enol tautomerization reaction.^[14] This reaction is catalyzed by 3beta-hydroxysteroid dehydrogenase/delta(5)-delta(4)isomerase.

Progesterone in turn (see lower half of figure to the right) is the precursor of the mineralocorticoid aldosterone, and after conversion to 17-hydroxyprogesterone (another natural progestogen) of cortisol and androstenedione. Androstenedione can be converted to testosterone, estrone and estradiol.

Pregenolone and progesterone can also be synthesized by yeast.^[15]

Laboratory

The Marker semisynthesis of progesterone from diosgenin.^[16]

An economical semisynthesis of progesterone from the plant steroid diosgenin isolated from yams was developed by Russell Marker in 1940 for the Parke-Davis pharmaceutical company (see figure to the right).^[16] This synthesis is known as the Marker degradation. Additional semisyntheses of progesterone have also been reported starting from a variety of steroids. For the example, cortisone can be simultaneously be deoxygenated at the C-17 and C-21 position by treatment with iodotrimethylsilane in chloroform to produce 11-keto-progesterone (ketogestin) which in turn can be reduced at position-11 to yield progesterone.^[17]

The Johnson total synthesis of progesterone.^[18]

A total synthesis of progesterone was reported in 1971 by W.S. Johnson (see figure to the right).^[18] The synthesis begins with reacting the phosphonium salt 7 with phenyl lithium to produce the phosphonium ylide 8. The ylide 8 is reacted with an aldehyde to produce the alkene 9. The ketal protecting groups of 9 are hydrolyzed to produce the diketone 10 which in turn is cyclized to from the cyclopentenone 11. The ketone of 11 is reacted with methyl lithium to yield the tertiary alcohol 12 which in turn is treated with acid to produce the tertiary cation 13. The key step of the synthesis is the π-cation cyclization of 13 in which the B-, C-, and D-rings of the steroid are simultaneously formed to produce 14. This step resembles the cationic cyclization reaction used in the biosynthesis of steroids and hence is referred to as biomimetic. In the next step the enol orthoester is hydrolyzed to produce the ketone 15. The cyclopentene A-ring is then opened by oxidizing with ozone to produce 16. Finally, the diketone 17 undergoes an intramolecular aldol condensation by treating with aqueous potassium hydroxide to produce progesterone.^[18]

Levels

Progesterone levels (black line) during the menstrual cycle

In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase. Progesterone levels tend to be < 2 ng/ml prior to ovulation, and > 5 ng/ml after ovulation. If pregnancy occurs, progesterone levels are initially maintained at luteal levels. With the onset of the luteal-placental shift in progesterone support of the pregnancy, levels start to rise further and may reach 100-200 ng/ml at term. Whether a decrease in progesterone levels is critical for the initiation of labor has been argued and may be species-specific. After delivery of the placenta and during lactation, progesterone levels are very low.

Progesterone levels are relatively low in children and postmenopausal women.^[19] Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.

Reference ranges for estradiol and progesterone in the menstrual cycle, expressed in mass and molar concentration. Because of slightly different molar mass, the relative concentrations differ somewhat. The scale is logarithmic.

Effects

Micrograph showing changes to the endometrium due to progesterone (decidualization) H&E stain.

Progesterone exerts its primary action through the intracellular progesterone receptor although a distinct, membrane bound progesterone receptor has also been postulated.^[20][21] Additionally, progesterone is a highly potent antagonist of the mineralocorticoid receptor (MR, the receptor for aldosterone and other mineralocorticosteroids). It prevents MR activation by binding to this receptor with an affinity exceeding even those of aldosterone and other corticosteroids such as cortisol and corticosterone.^[22]

Progesterone has a number of physiological effects which are amplified in the presence of estrogen. Estrogen through estrogen receptors upregulates the expression of progesterone receptors.^[23] Also, elevated levels of progesterone potently reduce the sodium-retaining activity of aldosterone, resulting in natriuresis and a reduction in extracellular fluid volume. Progesterone withdrawal, on the other hand, is associated with a temporary increase in sodium retention (reduced natriuresis, with an increase in extracellular fluid volume) due to the compensatory increase in aldosterone production which combats the blockade of the mineralocorticoid receptor by the previously elevated level of progesterone.^[24]

Reproductive system

Progesterone is sometimes called the "hormone of pregnancy",^[25] and it has many roles relating to the development of the fetus:

• Progesterone converts the endometrium to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal epithelium and cervical mucus, making it thick and impermeable to sperm. If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruation. Normal menstrual bleeding is progesterone-withdrawal bleeding.

• During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy.

• Progesterone decreases contractility of the uterine smooth muscle.^[25]

• In addition progesterone inhibits lactation during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production.

• A drop in progesterone levels is possibly one step that facilitates the onset of labor.

The fetus metabolizes placental progesterone in the production of adrenal steroids.

Nervous system

Progesterone, like pregnenolone and dehydroepiandrosterone, belongs to the group of neurosteroids. It can be synthesized within the central nervous system and also serves as a precursor to another major neurosteroid, allopregnanolone.

Neurosteroids affect synaptic functioning, are neuroprotective, and affect myelination.^[26] They are investigated for their potential to improve memory and cognitive ability. Progesterone affects regulation of apoptotic genes.

Its effect as a neurosteroid works predominantly through the GSK-3 beta pathway, as an inhibitor. (Other GSK-3 beta inhibitors include bipolar mood stabilizers, lithium and valproic acid.)

Other systems

• It raises epidermal growth factor-1 levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cells.

• It increases core temperature (thermogenic function) during ovulation.^[27]

• It reduces spasm and relaxes smooth muscle. Bronchi are widened and mucus regulated. (Progesterone receptors are widely present in submucosal tissue.)

• It acts as an antiinflammatory agent and regulates the immune response.

• It reduces gall-bladder activity.^[28]

• It normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy.

• It may affect gum health, increasing risk of gingivitis (gum inflammation) and tooth decay.

• It appears to prevent endometrial cancer (involving the uterine lining) by regulating the effects of estrogen.

Adverse effects

Progesterone can cause increased fluid retention which may result in epilepsy, migraine, asthma, cardiac or renal dysfunction. Blood clots may develop which can result in strokes and heart attacks which may lead to death or long-term disability; pulmonary embolus or breast cancer can also develop as a result of progesterone therapy. Progesterone is associated with an increased risk of thrombotic disorders such as thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis.^[29]

Common adverse effects include; cramps, abdominal pain, skeletal pain, perineal pain, headache, arthralgia, constipation, dyspareunia, nocturia, diarrhea, nausea, vomiting, joint pain, flatulence, hot flushes, decreased libido, thirst, increased appetite, nervousness, drowsiness, excessive urination at night. Psychiatric effects including depression, mood swings, emotional instability, aggression, abnormal crying, insomnia, forgetfulness, sleep disorders.^[29]

Less frequent adverse effects which may occur include; allergy, anemia, bloating, cramps, fatigue, tremor, urticaria, pain, conjunctivitis, dizziness, vomiting, myalgia, back pain, breast pain, difficult or painful intercourse, genital itching, genital yeast infection, upper respiratory tract infection, cystitis, dysuria, asthenia, xerophthalmia, syncope, dysmenorrhea, genital pruitis, premenstrual tension, gastritis, urinary tract infection, urinary tract infection, vaginal discharge, pharyngitis, sweating, hyperventilation, vaginal dryness, dyspnea, fever, edema, flu-like symptoms, gastrointestinal discomfort, gas, abdominal swelling, dry mouth, rhinitis, back pain, pruritis, rash, leg pain, skin discoloration, skin disorders, seborrhea, sinusitis, upper respiratory tract infection, asthma, acne, itching, painful or difficult urination, frequent urination.^[29]

Medical applications

The use of progesterone and its analogues have many medical applications—both to address acute situations, and to address the long-term decline of natural progesterone levels. Because of the poor bioavailability of progesterone when taken orally, many synthetic progestins have been designed. However, the roles of progesterone may not be fulfilled by the synthetic progestins which in some cases were designed solely to mimic progesterone's uterine effects.

Bioavailability

Progesterone is poorly absorbed by oral ingestion unless micronised and in oil, or with fatty foods; it does not dissolve in water. Products such as Prometrium, Utrogestan, Minagest and Microgest are therefore capsules containing micronised progesterone in oil - in all three mentioned the oil is peanut oil, which may cause serious allergic reactions in some people, but compounding pharmacies, which have the facilities and licenses to make their own products, can use alternatives. Vaginal and rectal application is also effective, with products such as ENDOMETRIN (progesterone) Vaginal Insert 100 mg, approved by the FDA in June 2007 to support embryo implantation and early pregnancy. Other products are CRINONE and PROCHIEVE bioadhesive progesterone vaginal gels (the first progesterone products FDA-approved for use in infertility and during pregnancy) and Cyclogest, which is progesterone in cocoa butter in the form of pessaries. Progesterone can be given by injection, but because it has a short half-life they need to be daily. Marketing of progesterone phamaceutical products, country to country, varies considerably, with many countries having no oral progesterone products marketed, but they can usually be specially imported by pharmacies through international wholesalers.

Progesterone can be absorbed through the skin when administered as a skin cream, thus avoiding the breakdown by the liver that occurs when it is ingested.^[30]

"Natural progesterone" products derived from yams, do not require a prescription. Wild yams contain a plant steroid called diosgenin, however there is no evidence that the human body can metabolize diosgenin into progesterone.^[31][32] Diosgenin can however be chemically converted into progesterone in the lab.^[16]

Specific uses

• Progesterone is used to support pregnancy in Assisted Reproductive Technology (ART) cycles such as In-vitro Fertilization (IVF). While daily intramuscular injections of progesterone-in-oil (PIO) have been the standard route of administration, PIO injections are not FDA-approved for use in pregnancy. A recent meta-analysis showed that the intravaginal route with an appropriate dose and dosing frequency is equivalent to daily intramuscular injections.^[33] In addition, a recent case-matched study comparing vaginal progesterone with PIO injections showed that live birth rates were nearly identical with both methods.^[34]

• Progesterone is used to control anovulatory bleeding. It is also used to prepare uterine lining in infertility therapy and to support early pregnancy. Patients with recurrent pregnancy loss due to inadequate progesterone production may receive progesterone.

• Progesterone is being investigated as potentially beneficial in treating multiple sclerosis, since the characteristic deterioration of nerve myelin insulation halts during pregnancy, when progesterone levels are raised; deterioration commences again when the levels drop.

• Vaginally dosed progesterone is being investigated as potentially beneficial in preventing preterm birth in women at risk for preterm birth. The initial study by Fonseca suggested that vaginal progesterone could prevent preterm birth in women with a history of preterm birth.^[35]

A subsequent and larger study showed that vaginal progesterone was no better than placebo in preventing recurrent preterm birth in women with a history of a previous preterm birth,^[36] but a planned secondary analysis of the data in this trial showed that women with a short cervix at baseline in the trial had benefit in two ways: a reduction in births less than 32 weeks and a reduction in both the frequency and the time their babies were in intensive care.^[37] In another trial, vaginal progesterone was shown to be better than placebo in reducing preterm birth prior to 34 weeks in women with an extremely short cervix at baseline.^[38] An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.^[39]

• Progesterone is used in hormone therapy for transsexual women and other women with intersex conditions - especially when synthetic progestins have been ineffective or caused side-effects - since normal breast tissue cannot develop except in the presence of both progestogen and estrogen. Mammary glandular tissue is otherwise fibrotic, the breast shape conical and the areola immature. Progesterone can correct those even after years of inadequate hormonal treatment. Research usually cited against such value was conducted using Provera, a synthetic progestin. Progesterone also has a role in skin elasticity and bone strength, in respiration, in nerve tissue and in female sexuality, and the presence of progesterone receptors in certain muscle and fat tissue may hint at a role in sexually-dimorphic proportions of those.

• Progesterone receptor antagonists, or selective progesterone receptor modulators (SPRM)s, such as RU-486 (Mifepristone), can be used to prevent conception or induce medical abortions.

Note that methods of hormonal contraception do not contain progesterone but a progestin.

Progesterone may affect male behavior.^[40]

Progesterone is starting to be used in the treatment of the skin condition hidradenitis suppurativa.^{[citation needed]}

Aging

Since most progesterone in males is created during testicular production of testosterone, and most in females by the ovaries, the shutting down (whether by natural or chemical means), or removal, of those inevitably causes a considerable reduction in progesterone levels. Previous concentration upon the role of progestagens (progesterone and molecules with similar effects) in female reproduction, when progesterone was simply considered a "female hormone", obscured the significance of progesterone elsewhere in both sexes.

The tendency for progesterone to have a regulatory effect, the presence of progesterone receptors in many types of body tissue, and the pattern of deterioration (or tumor formation) in many of those increasing in later years when progesterone levels have dropped, is prompting widespread research into the potential value of maintaining progesterone levels in both males and females.

Brain damage

Previous studies have shown that progesterone supports the normal development of neurons in the brain, and that the hormone has a protective effect on damaged brain tissue. It has been observed in animal models that females have reduced susceptibility to traumatic brain injury and this protective effect has been hypothesized to be caused by increased circulating levels of estrogen and progesterone in females.^[41] A number of additional animal studies have confirmed that progesterone has neuroprotective effects when administered shortly after traumatic brain injury.^[42] Encouraging results have also been reported in human clinical trials.^[43][44]

The mechanism of progesterone protective effects may be the reduction of inflammation which follows brain trauma.^[45]

See also

• Willard Myron Allen
• Endometrin
• Prometrium
• AKR1C1 - the enzyme that deactivates progesterone

References

Additional images

Steroidogenesis, showing progesterone among the progestagens in yellow area.

Pregnenolone   Deoxycorticosterone

External links

• MeSH Progesterone
• Kimball JW (2007-05-27). "Progesterone". Kimball's Biology Pages. http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Progesterone.html. Retrieved 2008-06-18. 
• "Progesterone Resource Center". PMS, Menopause, and Progesterone Resource Center. Oasis Advanced Wellness, Inc. http://www.pms-menopause-progesterone.org/progesterone/. Retrieved 2008-06-18. 
• Infertility - possible Treatments and Causes
• Ovulation and How it happens, Triggers and How to Help it Occur
• General discussion document on Progesterone, its uses and applications

From Wikiversity

Progesterone is a hormone that is normally found in women and it reaches particularly high levels during pregnancy. Progestins are synthetic drugs that mimic the biological actions of progesterone and they have been widely prescribed to women. This learning project allows Wikiversity participants to explore health-related topics that involve progesterone and synthetic drugs that act on progesterone receptors.

Progesterone, progestins and breast cancer

The Wikipedia articles on breast cancer and progestins do not mention that breast cancer rates appear to be increased by progestin use. Wikipedia articles for the Women's Health Initiative and Hormone replacement therapy do mention some of the clinical trial results that link progestin use to increased breast cancer risk. Recent studies suggest mechanisms by which progesterone receptors might stimulate breast tumor growth.^[1] The Wikipedia article on Bioidentical hormone replacement therapy raises the question: might progesterone use pose less breast cancer risk than use of synthetic progestins?^[2]

Why are progestins so widely prescribed?

Progestins are widely used by both younger women and older women. Younger women of reproductive age often use progestins for hormonal contraception. Older women have frequently been prescribed combinations of estogen and progestins as Hormone replacement therapy when endogenous levels of estrogen decline. Combined estrogen and progestin administration is used to limit the incidence of estrogen supplement-induced endometrial cancer.

News reports

This is a running list of news reports related to progestrone, progestins and related health issues such as breast cancer.

Lawsuits

October 30, 2007. "Wyeth is facing more than 5,000 lawsuits from those who believe they were harmed by the hormone replacement drugs, which have been used by millions of women to control the effects of menopause."^[3] Wyeth is the manufacturer of Premarin and Prepro, a mixture of medroxyprogesterone and Premarin.

The Women's Health Initiative estrogen-plus-progestin study reported an increased rate of breast cancer for women using Prempro.^[4] The Food and Drug Administration now requires that the Women's Health Initiative results for breast cancer be provided to patients who use Prempro (Label).

Brest cancer incidence

December 15, 2006. Following the release of results from the WHI Prempro clinical trial (see above), "Within six months, the drug's sales had fallen by 50 percent." Breast cancer incidence also declined during this time: "The reason, researchers believe, may be that millions of women during that time abandoned hormone treatment for the symptoms of menopause"^[5]

Epidemiological studies report that since women started to become aware of the risks associated with progestin use, decreases in incidence of breast cancer parallels the decline in progestin use, consistent with the known increased risk of breast cancer among women who use progestins.^[6]

Using progesterone rather than progestins

January 16, 2007. The North American Menopause Society (NAMS) is a nonprofit organization concerned with menopause. T.V. correspondent Dr. Emily Senay reported that the NAMS has urged doctors not to prescribe natural hormones like progesterone for menopausal women^[7] Large clinical trials have not been performed to test the efficacy and safety of natural hormones like progesterone for treating the symptoms of menopause.

Who would pay for clinical research studies on progesterone? One possibility is that government funding would be provided in an attempt to find alternatives to synthetic progestins, but is there a level playing field for discussion of such studies when drug companies make large profits from synthetic progestins? The International Academy of Compounding Pharmacists has suggested that The North American Menopause Society is not an independent voice because it is supported by progestin manufacturers.North American Menopause Society’s Ties to Wyeth Pharmaceuticals

One recent reviewer concluded that there needs to be more research on bioidentical hormones and that there is, "evidence to support their preferred use over that of their synthetic cousins."^[8] Other reviewers have reached the opposite conclision. ^[9]

A major concern for use of progesterone rather than synthetic progestins is that progesterone is rapidly metabolized in the body. There are many different formulations of mixtures of estrogen and progesterone and various methods for administering them. There has been concern about quality control for progesterone both in terms of variability in amounts and efficiency of absorption. Some women have used bioidentical hormone treatments for extended periods of time without monitoring for possible stimulation of uterine tissue growth. ^[10] Women should not assume that bioidentical hormone treatments are safe just because they use natural hormones. Supplements containing natural estrogen can cause endometrial cancer.

References

1. ↑ Progesterone Receptors Upregulate Wnt-1 To Induce Epidermal Growth Factor Receptor Transactivation and c-Src-Dependent Sustained Activation of Erk1/2 Mitogen-Activated Protein Kinase in Breast Cancer Cells by Emily J. Faivre and Carol A. Lange in Mol Cell Biol. (2007) Volume 27 pages 466–480.
2. ↑ Progestins and progesterone in hormone replacement therapy and the risk of breast cancer by Carlo Campagnoli, Françoise Clavel-Chapelon, Rudolf Kaaks, Clementina Peris, and Franco Berrino in J Steroid Biochem Mol Biol. (2005) Volume 96, pages 95–108.
3. ↑ Judge dismisses hormone case against Wyeth, Reuters, 30 October, 2007.
4. ↑ "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial" by J. E. Rossouw, G. L. Anderson and R.L. Prentice in Journal of the American Medical Association (2002) Volume 288, pages 321-333.
5. ↑ Breast cancer rates drop 15% from August 2002 to December 2003 by Gina Kolata December 15, 2006, in International Herald Tribune.
6. ↑ "Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin" by G. A. Colditz in Breast Cancer Res. (2007) Volume 9, page 108.
7. ↑ Testing Of Bioidentical Hormones Urged. The Early Show medical correspondent Dr. Emily Senay and co-anchor Julie Chen. January 16, 2007
8. ↑ A comprehensive review of the safety and efficacy of bioidentical hormones for the management of menopause and related health risks by Deborah Moskowitz in Altern Med Rev. (2006) Volume 11, pages 208-223.
9. ↑ "Bioidentical hormone therapy: a review of the evidence." by M. Cirigliano in J. Womens Health (Larchmt) (2007) Volume 16, pages 600-631.
10. ↑ Three cases of endometrial cancer associated with "bioidentical" hormone replacement therapy by John A Eden, Neville F Hacker and Michael Fortune in Med J Aust. (2007) Volume 187, pages 244-245.

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