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hormone
progesterone
nutrition

definition

Progesterone:

» metabolism:
• Progesterone is derived from Pregnenolone and is a precursor to other hormones, including estrogens, testosterone, aldosterone, and corticosteriods. (See Pathways Diagram)
• During a normal reproductive cycle, the corpus luteum in the ovary should produce 20-40 mg of progesterone daily following ovulation. Disruption of ovulation can contribute to an imbalance between estrogen and progesterone, as progesterone levels do not rise as expected during periods of anovulation.
• Progesterone can act as an estrogen antagonist in the breast and uterus, decreasing cell division, increasing cellular maturity, and inhibiting the replenishment of estrogen receptors.
• Progesterone has also been shown to stimulate 17 beta-dehydrogenase, which allows for the conversion of estradiol to a less active metabolite.
• The presence of progesterone in the body sensitizes estrogen receptor sites, enabling circulating estrogen to work better.
• Due to anovulatory cycles, progesterone levels typically decline first peri-menopausally, followed by a decline in estrogen. The term anovulatory refers to cycles where ovulation does not occur, and consequently there is no corpus luteum to secrete progesterone. Progesterone levels fall to near zero levels due to anovulatory cycles, while estrogen levels only decline to about 40-60 % of pre-menopausal levels. This precipitous drop in progesterone levels can lead to an imbalance between estrogen and progesterone, causing a relative estrogen dominance within the body.
• Progesterone has a number of important roles relative to menopause. Progesterone is the natural balancer to estrogen, as well as being necessary for optimum estrogen utilization. In addition to normalizing both blood sugar levels and water metabolism, progesterone also has a calming effect on the central nervous system.
• Progesterone helps the body build new bone by increasing the activity of osteoblasts.

» function:
Progesterone:
• is a precursor of other sex hormones, including estrogen and testosterone
• maintains secretory endometrium (uterine lining)
• is necessary for the survival of the embryo and fetus throughout gestation
• protects against fibrocystic breasts
• is a natural diuretic
• helps use fat for energy
• functions as a natural antidepressant
• helps thyroid hormone action
• normalizes blood clotting
• restores sex drive
• helps normalize blood sugar levels
• normalizes zinc and copper levels
• restores proper cell oxygen levels
• has a thermogenic (temperature-raising) effect
• protects against endometrial cancer
• helps protect against breast cancer
• builds bone and is protective against osteoporosis
• is a precursor of cortisone synthesis by adrenal cortex.

» deficiency:
• Premenstrual Syndrome
• Perimenopause

» therapeutics:
• Breast cancer: Several clinical trials following women using estrogen with progesterone showed progesterone adequately opposed the increased risk for breast cancer imposed by estrogen. Progesterone can act as an estrogen antagonist in the breast and uterus, decreasing cell division, increasing cellular maturity, and inhibiting the replenishment of estrogen receptors. Progesterone has also been shown to stimulate 17 beta-dehydrogenase, which allows for the conversion of estradiol to a less active metabolite. One study demonstrated protective effects of progesterone similar to that of Tamoxifen in treating breast cancers
Cardiovascular disease: Natural progesterone may have a protective effect on the heart. Some very recent research showed that natural progesterone helped reduce spasms of the coronary arteries, which is relevant to reducing the risk of heart attacks. Blood vessel occlusion by cholesterol plaques combined with vasoconstriction can severely restrict blood flow to the heart, resulting in a "heart attack". In a study by Miyagawa, et al, progesterone plus estradiol was protective against vasospasm, whereas estradiol plus medroxyprogesterone allowed vasospasm, concluding that medroxyprogesterone increases risk of coronary vasospasm, while natural progesterone does not. (Miyagawa, K, Rosch, J, Stanczyk, F, and Hermsmeyer, K. Nature Medicine, Vol. 3, No. 3, 324-327.)
Endometriosis: Estrogen initiates endometrial cell proliferation and the formation of blood vessel accumulation in the endometrium; the aim of treatment is to block this monthly estrogen stimulus to the aberrant endometrial islets. Progesterone stops further proliferation of endometrial cells. Transdermal progesterone supplementation at _ tsp (20 mg progesterone) twice daily from day 7 to day 28 of the reproductive cycle can be used to block endometrial priming by estrogen. This treatment requires patience, as 4-6 months use may be required for maximum benefit.
Fibrocystic breast disease: Fibrocystic breast disease may be caused by excessive estrogenic stimulation of the breasts due to abnormal hormone levels or by an exaggerated response by hypersensitive tissues to normal hormone levels. The administration of natural progesterone is suggested by Dr. John Lee, MD to be a protective therapy that can reduce breast tenderness and fibrocystic changes.
Infertility: One clinical study showed that infertile women with endogenous progesterone deficiencies have a five-fold increased risk of pre-menopausal breast cancer compared to women with normal hormone levels.
Perimenopause and menopause: Progesterone levels fall to near zero levels due to anovulatory cycles, while estrogen levels only decline to about 40-60 % of pre-menopausal levels. This precipitous drop in progesterone levels can lead to an imbalance between estrogen and progesterone, causing a relative estrogen dominance within the body. Many women find that supplementing progesterone alleviates many of the menopausal symptoms they are experiencing. Using progesterone alone or in combination with estrogens poses a significantly reduced risk for endometrial cancer than does the use of unopposed estrogen. (Smith, DC, Prentice, R, Thompson, DJ, et al. Endocr Rev 1990:386-398)
Osteoporosis: Progesterone helps the body build new bone by increasing the activity of osteoblasts. Progesterone increases bone building activity, while estrogen primarily slows down bone loss.
Premenstrual syndrome: Many symptoms related to PMS can be attributed to "estrogen dominance," a condition of relative excess estrogen activity in the body. This can be caused by too much estrogen, or by sub-normal levels of progesterone in the body. While there have been many claims as to the value of progesterone in treating PMS, controlled clinical trials have failed to consistently demonstrate the superiority of progesterone. The studies that did demonstrate a beneficial effect of progesterone therapy have used dosages that far exceed the normal levels for progesterone and for the estrogen-to-progesterone ratio. 200-400 mg twice daily as a vaginal or rectal suppository, from fourteen days before the expected onset of menstruation until the onset of vaginal bleeding). (Baker, ER, et al. J Assist Reprod Genet 12(3) (1995): 205-209; Magill, PJ, Br J Gen Pract 45(400) (1995): 589-593) (Freeman, E, at al. JAMA 264(1990): 349-353; Maddocks, S, et al. Am J Obstet Gynecl 154 (1986): 573-581; Andersch, B, and Hahn, LJ. Psychosom Res 29 (1985): 489-493; Dennerstain, L, at al. Br Med J 290(1985): 1617-1621; Baker, ER, et al. J Assist Reprod Genet 12(3) (1995): 205-209; Magill, PJ. Br J Gen Pract 45(400) (1995): 589-593.)

» dosage:
• The proper amount of progesterone for a woman should be determined in consultation with a doctor of natural medicine. Research with micronized progesterone, the, oral form of natural progesterone, has utilized 200 mg per day. (Hargrove, JT, Maxson, WS, Wentz, AC, Burnett, LS. Obstetrics and Gynecology, Vol. 73, No. 4, April 1989, 606-12.) However, when prescribed by physicians experienced in its usage, topical natural progesterone is often dosed in much lower amounts, such as 20-4O mg per day
• Many sources suggest that the best areas to apply the transdermal progesterone cream (450 mg P/oz) are the palms, inner arms, inner thighs, abdomen, and chest, rotating the areas applied. On the other hand, some sources suggest that applying the cream intravaginally is more effective than simply applying the cream to the skin because applying the cream to the skin (nonmucous membranes) may result in poor absorption.
• Transdermal progesterone cream (450 mg P/oz) is usually applied twice daily due to the short half-life of progesterone in the blood.
• Ultimately dosage varies for each individual and for the same individual through the course of usage.
• Progesterone levels can be monitored through a saliva test.

The following are general recommendations that should be confirmed or modified in concert with a health care provider. Salivary hormonal testing may provide valuable information to help assess need for natural progesterone and to evaluate the amount of transdermal progesterone cream (450 mg P/oz) to use.

For women who are trying to conceive while addressing their endometriosis symptoms, the recommended usage would be:
Begin using transdermal progesterone cream (450 mg P/oz) after ovulation. Adjust the following recommendations to coincide with patient's ovulation day.
Days 14 ( ovulation) - 20: use 1/4 teaspoon of progesterone (twice a day).
Days 21-27: use 1/2 teaspoon progesterone (twice a day).
Days 1-14: do not use progesterone.

Women in their reproductive years (e.g. for PMS, painful cramping with periods, and/or menstrual irregularities -- still ovulating):
Begin using transdermal progesterone cream (450 mg P/oz) after ovulation. Ovulation usually occurs 14 days before your period begins. Count the first day of bleeding as day one of the cycle. Assuming a 28 day cycle, that means that ovulation will probably occur on day 14. Adjust the following recommendations to coincide with the patient's ovulation day.
Days 14 ( ovulation) - 20: use 1/4 teaspoon of transdermal progesterone cream (450 mg P/oz) twice a day.
Days 21-27: use 1/2 teaspoon transdermal progesterone cream (450 mg P/oz) twice a day.
Days 1-14: do not use transdermal progesterone cream (450 mg P/oz).

Women who are perimenopausal (still menstruating, but with menopausal symptoms and/or PMS -- not ovulating):
Day 1 (first day of bleeding) - 6: do not use transdermal progesterone cream (450 mg P/oz)
Day 7-20: use 1/4 teaspoon transdermal progesterone cream (450 mg P/oz) twice a day
Day 21-27: use up to 1/2 teaspoon if necessary for PMS symptoms. If no PMS symptoms occur, continue using 1/4 teaspoon twice a day.
If the period begins early, STOP using the transdermal progesterone cream (450 mg P/oz) while bleeding, count the first day of bleeding as day one, and begin the cycle again.
If the period is late, the cream should be used for up to 3 weeks (day 28 of your cycle), followed by a week off. If the period has not started by the end of the week, resume the cream until the period starts. STOP the cream when the period begins, count the first day of bleeding as day one of the cycle, and begin the cycle over again.

Women who are post-menopausal for bone health:
Choose a calendar day (e.g. first day of the month), or the first day of the lunar month, as day one
Days 1-25: use 1/4 teaspoon of transdermal progesterone cream (450 mg P/oz) twice a day.
Days 25-30 or 31(or 28): do not use transdermal progesterone cream (450 mg P/oz).

For severe menopausal symptoms: use up to 1/2 teaspoon a day according to the same schedule.

» forms:
• Transdermal progesterone cream (450 mg P/oz)
• Micronized.
• Combined with other hormones such as estriol, estradiol and/or testosterone.

A Note on sources of progesterone:
"Natural" progesterone refers to a molecule that is identical to the progesterone molecule that the body makes. Most natural progesterone products today are synthesized from the steroidal saponins (such as diosgenin) found in wild yam (Dioscorea villosa) or from soy using a process developed by Russell Marker in the 1930's. Marker's pioneering research made progesterone widely available for the first time using this cost-effective method.

Synthetic "progestins" or "progestogens," do not exactly duplicate the body's own progesterone molecule. They mimic the body's progesterone closely enough to bind to progesterone receptor sites, but they do not deliver the full range of "messages" that a natural progesterone molecule would. A synthetic progestin (i.e. medroxyprogesterone acetate, norethindrone), for example, does decrease the build up of the uterine lining (a function of natural progesterone) as well as cause withdrawal bleeding, but has little or no effect on water metabolism or blood sugar stabilization, which are part of natural progesterone's functions.

Synthetic progestins do not increase the serum or salivary levels of progesterone. In contrast, transdermal (skin) applications of natural progesterone will increase salivary and serum levels of progesterone.

Synthetic progestins also tend to produce many well-known side effects, including elevated LDL cholesterol and decreased HDL cholesterol levels. Other side effects reported with synthetic progestins include bloating, breast tenderness, depression, and mood swings.

Many companies today are producing "wild yam" creams that contain a concentrated extract of wild yam, Dioscorea villosa. Mexican wild yam is a source compound known as diosgenin that can be converted in a laboratory environment progesterone and to the hormone. However, the body does not have the ability to convert wild yam extract into progesterone. The body may absorb wild yam extract through the skin, which may have some effect on menopausal symptoms, yet research on both oral and skin applications of wild yam extract demonstrate no change in progesterone levels in the body. (Dollbaum, CM. Townsend Letter for Doctors and Patients Oct 1995;104; Araghiniknam, M, Chung, S, Nelson-White, T, et al. Life Sci 1996;l 1:147-57.)

» side effects:
• Side effects, although generally mild, have been reported. In one of the more recent double-blind studies that did show a positive effect of progesterone therapy (400 mg twice a day by vaginal or rectal administration), adverse events were reported by 51% of the patients in the progesterone treatment group, compared to 43% in the placebo group. Irregularity of menstruation, vaginal itching, and headache were reported more frequently by the women who took the progesterone. (Magill, PJ. Br J Gen Pract 45(400) (1995): 589-593.)
• Various anecdotal evidence seems to indicate that topical progesterone might somehow cause drowsiness in some women and that such symptoms might be aggravated by larger doses of the progesterone.

» toxicity:
• No reports of toxicity for natural progesterone were found in any of the sources reviewed.

» contraindications:
• None known, though caution may be indicated in cases of breast cancer or other situations where conversion of excess progesterone to estrogen might have adverse effects. Nevertheless, no studies have been found that find natural progesterone poses a risk for women with a history of breast cancer.

» interactions:
• No reports of drug interactions were found in any of the sources reviewed.
• Progesterone can act as an estrogen antagonist in the breast and uterus.

footnotes

Affinito P, Di Carlo C, Di Mauro P, Napolitano V, Nappi C. Endometrial hyperplasia: efficacy of a new treatment with a vaginal cream containing natural micronized progesterone. Maturitas 1994 Dec;20(2-3):191-198.
Abstract: Seventy-eight premenopausal women affected by benign endometrial hyperplasia (60 simple and 18 complex) were treated from the 10th to the 25th day of the menstrual cycle with a vaginal cream containing 100 mg of natural micronized progesterone in polyethylene glycol base. The treatment lasted 3 months in 58 patients and 6 in the other 16 patients. Four patients were lost from the study. We observed a total of 67 complete regressions (90.5%) of which 58 (78.3%) occurred in the first 3 months and 9 (11.5%) after 6 months of treatment. Simple hyperplasia showed a significantly higher response to treatment in comparison with the complex type (P < 0.001). The most frequent endometrial pattern detected in the patients in whom hyperplasia regressed was of a secretive type. Recurrence of hyperplasia occurred in 1 out of 58 (1.72%) patients at the 3rd month and in 3 out of 49 (6.1%) patients at the 6th month after treatment. There were no significant differences between the two hystological groups in the percentage of recurrence. During treatment we observed a significant reduction of the amount, duration and frequency of the menstrual bleeding. Minimal side-effects were observed. In conclusion, for its effectiveness and safety, vaginal administration of natural micronized progesterone seems to be an interesting approach to benign endometrial hyperplasia, particularly indicated in women also affected by metabolic disorders.

Andersch, B, and Hahn, LJ. Progesterone Treatment of Premenstrual Tension - A Double Blind Study. Psychosom Res 29 (1985): 489-493.

Araghiniknam, M, Chung, S, Nelson-White, T, et al. Antioxidant activity of dioscorea and dehydroepiandrosterone (DHEA) in older humans. Life Sci 1996;11:147-157.

Baker, ER, et al. Efficacy of Progesterone Vaginal Suppositories in Alleviation of Nervous Symptoms in Patients with Premenstrual Syndrome. J Assist Reprod Genet 12(3)(1995): 205-209.

Brooks, PG. The relationship of estrogen and progesterone to breast disease. Journal of Reproductive Medicine, 1984, 29(7): supp.

Buzdar, AU. Progestins in cancer treatment. In: Stoll BA, ed. Endocrine management of cancer, New York: Karger, 1-15, 1988.

Chang, KJ, et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertility and Sterility, Vol. 63, No. 4. April 1995.
Abstract: The effect of transdermal estradiol (1.5 mg), transdermal progesterone (25 mg), and combined transdermal estradiol and progesterone (1.5 mg and 25 mg) on human breast epithelial cell cycles was evaluated in vivo. Results demonstrated that estradiol significantly increases cell proliferation, while progesterone significantly decreases cell replication below that observed with placebo. Transdermal progesterone was also shown to reduce estradiol-induced proliferation.

Cipolla L, Zagni R, Giannetta G, Ferrante B, Soliani A. [New pharmacological approach to therapy of perimenopausal meno-metrorrhagia. Vaginal use of progesterone]. Minerva Ginecol 1994 Nov;46(11):619-624.

Abstract: The authors evaluate the effectiveness of a therapy based on natural progesterone to be employed as a vaginal cream in the treatment of meno-metrorrhagia in peri-menopause in 40 patients who were not prepared to consider surgery as a solution for their problems. In the polycentric out-patient study this new preparation has proved to be efficacious and to induce a regression of the endometrial hyperplasia in more than 90% of patients subject to five months' treatment.

Cowan, LD, Gordis, L, Tonascia, JA, et al. Breast cancer incidence in women with a history of progesterone deficiency. American Journal of Epidemiology, 114:209-217, 1981.
Abstract: 1,083 infertile women were followed for 14-34 years. Those who were deficient in progesterone showed a five-fold greater incidence of premenopausal breast cancer.

Dennerstain, L, at al. Progesterone and the Premenstrual Syndrome: A Double Blind Crossover Trial. Br Med J 290(1985): 1617-1621.

Dollbaum, CM. Lab analyses of salivary DHEA and progesterone following ingestion of yam-containing products. Townsend Letter for Doctors and Patients Oct 1995;104.

Freeman, E, et al. Ineffectiveness of Progesterone Suppository Treatment for Premenstrual Syndrome. JAMA 264(1990): 349-353.

Gambrell ,RD Jr. Use of progestogen therapy. American Journal of Obstetrics and Gynecology, 156:1304-13, 1987.
Abstract: In a study of over 5,000 postmenopausal women, data indicated that when progesterone was added to estrogen therapy, there was a significant drop in breast cancer occurrence.

Gambrell, RD Jr. Editorial: Hormone replacement therapy in patients with previous breast cancer. Menopause, Vol. 2, No. 2, 55-57, 1995.

Hargrove, JT, Maxson, WS, Wentz, AC, Burnett, LS. Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone. Obstetrics and Gynecology, Vol. 73, No. 4, April 1989, 606-12.

Hargrove JT, Osteen KG. An alternative method of hormone replacement therapy using the natural sex steroids. Infert Repro Med Clin NAm 1995;6:653-74.

Inoh, A, Kamiya, K, Fuji, Y, Yokoro, K: Protective effects of progesterone and tamoxifen in estrogen-induced mammary carcinogenesis in ovariectomized W/FU rats. Jpn J Cancer Res, Vol. 76, 699-704, August 1995.

Laidlaw ,IJ, Clarke, RB. The proliferation of normal breast tissue implanted into athymic nude mice is stimulated by estrogen, but not by progesterone. Endocrinology, 136(1):164-71, January 1995.
Abstract: Normal human breast tissue was implanted subcutaneously into athymic nude mice. The mice were then treated with estradiol or progesterone such that serum levels approximated those seen in normal menstruating women. Immunocytochemical measures were made of proliferative activity and steroid receptor expression of the tissue implants. It was found that physiologic levels of estradiol significantly stimulated the proliferation of human breast epithelial cells and increased progesterone receptor expression 10-20-fold. Progesterone failed to effect proliferation alone or after estradiol priming.

Lee, John and Hopkins, Virgina. What Your Doctor May Not Tell You About Menopause. Warner Books, NY: 1996.

Leis, HP: Endocrine prophylaxis of breast cancer with cyclic estrogen and progesterone. Intern. Surg., 45: 496-503, 1966.

Maddocks, S, et al. A Double-Blind Placebo-Controlled Trial of Progesterone Vaginal Suppositories in the Treatment of Premenstrual Syndrome. Am J Obstet Gynecl 154 (1986): 573-581.

Magill, PJ. Investigation of the Efficacy of Progesterone Pessaries in the Relief of Symptoms of Premenstrual Syndrome. Progesterone Study Group. Br J Gen Pract 45(400) (1995): 589-593.

Miyagawa, K, Rosch, J, Stanczyk, F, and Hermsmeyer, K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nature Medicine, Vol. 3, No. 3, 324-327.

Mohr ,PE, Wang, DY, Gregory, WM, Richards, MA, Fentiman, IS. Serum progesterone and prognosis in operable breast cancer. British Journal of Cancer, 73: 1532-1533, 1996.
Abstract: Higher blood levels of progesterone measured during surgical treatment of breast cancers were associated with significantly better survival, especially in women who were node-positive (P<0.01). There was no significant relationship between E2 levels and survival. This study demonstrated that a higher level of progesterone at time of excision is associated with improved prognosis in women with operable breast cancer.

Nappi C, Affinito P, Di Carlo C, Esposito G, Montemagno U. Double-blind controlled trial of progesterone vaginal cream treatment for cyclical mastodynia in women with benign breast disease. J Endocrinol Invest 1992 Dec;15(11):801-806.
Abstract: The clinical effectiveness and safety of vaginal micronized progesterone treatment in mastodynia were evaluated in a double-blind placebo controlled study. Eighty regularly menstruating women affected by severe cyclical mastodynia were randomly assigned to two groups of 40 patients. One group was treated for 6 cycles from the 19th to the 25th day of the cycle with 4 g of vaginal cream containing 2.5% natural progesterone. The other group was similarly treated with placebo. The treatment was preceded by a control cycle. All patients reported every day their breast pain on a 100 mm visual linear analogue scale (VAS). The response of breast tenderness and nodularity to treatment was assessed by clinical examination. Vaginal progesterone resulted significantly more efficacious than placebo in reducing mean ratings of breast pain on VAS and mean scores of breast tenderness to touch. Success of treatment, defined as reduction greater than 50% of basal mean score of breast pain on VAS, was achieved in the 64.9% of patients treated with progesterone and in the 22.2% of patients receiving placebo (p < 0.01). Conversely, at the end of treatment, the improvement in breast nodularity showed a not statistically significant difference between the two groups. No major side-effects were detected.

Prior JC. Progesterone as a bone-trophic hormone. Endocr Rev 1990; 11:386-98.

Sitruk-Ware, R, Seradour, B, and Lafaye, C. Treatment of Benign Breast Diseases by Progesterone Applied Topically. Percutaneous Absorption of Steroids, Ed. Mauvais-Jarvis P, C Vickers, FH, Wepierre , J. Academic Press, 1980.

Smith DC, Prentice R, Thompson DJ, et al. Association of exogenous estrogen and endometrial carcinoma. NEJM 1975;293:l 164-67.

Veronesi, U, et al. Effect of menstrual phase on surgical treatment of breast cancer, Lancet, Vol. 343, June 18, 1994.

Zaffaroni L, Costa P, Vinci GW. [Topical progesterone as support for the luteal phase in induced cycles].

Minerva Ginecol 1997 Jul;49(7-8):361-364.
Abstract: Efficacy and tolerability of 2.5% natural vaginal progesterone as luteal phase support in pharmacologically induced cycles has been evaluated. MATERIALS AND METHODS: On the basis of the administered therapy, the population studied was subdivided at random into four different groups. Sixty patients came to the Sterility Autonomous Department of the Niguarda Ca' Granda Hospital in Milan from November 1994 to January 1996. Both ultrasonographic and plasmatic hormonal parameters have been evaluated on a monthly basis. RESULTS: The plasma progesterone levels and ultrasonographic endometrial thickness average values resulted more important in groups treated with topical progesterone; in these same groups a greater percentage of pregnancies was observed. CONCLUSIONS: The results obtained demonstrated that the drug studied can be recommended as a valid luteal phase support in pharmacologically induced cycles.


Note: A special thanks to Deborah Moskowitz, N.D., and the staff of Professional and Technical Services, Inc., Portland, OR, for their assistance in assembling some of the material for this topic.