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Hormone Replacement Therapy in Women

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Introduction: Is Hormone Replacement Therapy Safe?

The use of hormone replacement therapy has been a subject of controversy over many years, and the use of hormones has increased at a substantial rate in recent times. Hormone therapy for women is used to treat the symptoms related to reduction in estrogen and progesterone production which occurs with aging. Menopause is defined as a lack of menstruation for 12 months which occurs between the ages of 45 and 55, but on average, at the age of 51. Menstruation is often irregular at first and skips a few months, but then occurs with lower frequency until menopause is officially established. During the transition to menopause, a woman begins to experience hot flashes, insomnia, cognitive difficulty, mood swings, anxiety, fatigue, painful intercourse, and low libido.

 

Outcomes of the Women’s Health Initiative (WHI) trial (1):

A large group of post-menopausal women in good overall general health between the ages of 50 and 79 years were treated with conjugated estrogens 0.625 mg/day, conjugated estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day, or placebo. This trial was discontinued after 5.2 years when women were found to have a higher risk of adverse effects of hormone therapy compared to placebo.

 

Outcomes of estrogen and progestin compared to placebo in the WHI:

Higher rates of stroke, heart attack, breast cancer, and thromboembolism (deep venous thrombosis and pulmonary embolism) were associated with use of estrogen and progestin compared to placebo. Those over 65 years of age on hormones experienced less fractures, lower risk of endometrial cancer, and lower risk of colon cancer. There was no improvement in cognitive impairment, and there was an increase in risk of dementia in women 65 years of age or older.

The WHI study found that for every 10,000 women using estrogen-progestin combination (Prempro), 5 years of continuous use resulted in the following compared to placebo:

 

Outcomes of using estrogen only compared to placebo in the WHI:

Estrogen alone increased the risk of stroke and thromboembolism (deep venous thrombosis and pulmonary embolism), but did not change the risk of a heart attack and colorectal cancer compared to placebo. The effect of estrogen alone on breast cancer risk was unknown, but estrogen alone reduced the risk of having a fracture.

 

Additional Information about the WHI:

Frequently asked questions for this study may be found at: http://www.nhlbi.nih.gov/whi/whi_faq.htm

 

Follow up data from the WHI trial:

Hormone therapy started earlier in menopause: Hormone therapy that is started earlier in menopause at least by the age of 60 may result in a lower risk of adverse outcomes as opposed to starting it after the age of 60 (2). Salpeter, SR et al reported in a meta-analysis that hormone therapy lowered the risk of cardiac events in women less than 10 years from menopause or age under 60, but women who were older did not have this benefit (17). This meta-analysis also noted an increase in cardiac events in older women during the first year, but then a lower risk of cardiac events was seen after 2 years (17). Salpeter, SR et al also reviewed mortality data in a separate meta-analysis and found that women on hormone replacement therapy under age 60 had a lower mortality, but did not affect mortality in women over age 60 (18).

 

Hormone replacement therapy and endometrial cancer:

After over 13 years of follow-up since the WHI started, it was found that endometrial cancer risk was lowered by 35%. (10).

 

U.S. Food and Drug Administration (FDA) advises on hormone replacement therapy:

FDA indications for hormone replacement therapy:

FDA recommends that only FDA-approved hormone therapies be used for the treatment of vasomotor symptoms such as hot flashes and vaginal or vulvar atrophy, and not solely for the prevention of heart disease or osteoporosis. The FDA advises that hormonal therapy be used at the lowest dosage able to control symptoms for the shortest period of time. Hormonal therapy may be considered in women with osteoporosis unable to take other non-hormonal osteoporosis medications. (3)

 

FDA-approved hormone products:

The FDA has expressed that using FDA approved hormone therapy products available at retail pharmacies may be more safe than non-FDA approved or compounded hormones. Non-FDA approved hormones may not have strict oversight to ensure standardized or consistent doses of hormones. FDA-approved hormone products include (adapted from the FDA, Estrogen and Estrogen with Progestin Therapies for Postmenopausal Women) Alora (estradiol transdermal system), Angeliq (drospirenone and estradiol), Climara (estradiol transdermal system), Climara Pro (estradiol/levonorgestrel transdermal system), Combipatch (estradiol; norethindrone acetate transdermal system), Delestrogen (estradiol valerate injection), Enjuvia (synthetic conjugated estrogens), Estraderm (estradiol transdermal system), Estrasorb (estradiol topical emulsion), femhrt (norethindrone acetate/ethinyl estradiol tablets), Femring (estradiol acetate vaginal ring), Prefest (estradiol/norgestimate), Premarin (conjugated estrogens tablets),  Premarin Intravenous (conjugated estrogens for injection),  Premarin Vaginal Cream (conjugated estrogens),  Prempro/Premphase (conjugated estrogens/medroxyprogesterone acetate tablets), Vivelle (estradiol transdermal system), and Vivelle-Dot (estradiol transdermal system). (3)

 

Contraindications for the use of hormone replacement therapy:

The FDA states that hormone replacement therapy should not be used in abnormal bleeding of the genital area, patients with breast cancer in the past or present, suspected breast cancer, neoplasia suspected or known to be related to estrogen, present or past pulmonary embolism or deep venous thrombosis, myocardial infarction or stroke currently or within the past year, liver disease or elevated liver function tests, allergy to any ingredients, and current or possible pregnancy. (12)

 

Adverse effects of hormone replacement therapy:

The FDA has published the adverse effects of hormone replacement therapy which may include uterine cancer , breast cancer, ovarian cancer, stroke, myocardial infarction, pulmonary embolism, deep venous thrombosis, dementia, gallbladder problems, painful breasts, abnormal mammogram, abnormal vaginal bleeding, loss of hair, abdominal pain, nausea, and vomiting (3). Avoid exposure of estrogen to children and pets as breast and nipple enlargement has been reported.

 

Recommendations of the U.S. Preventive Services Task Force (USPSTF) for Menopausal Hormone Therapy:

It is against the recommendation of the USPSTF to treat postmenopausal women with combinations of estrogen and progestin for the prevention of chronic illnesses in postmenopausal women. The USPSTF advises against the use of estrogen in postmenopausal women with hysterectomy for prevention of chronic illness. The USPSTF reviewed trials authored between 2002 and 2012 which covered the use of hormone therapy in postmenopausal women. The perspective of the USPSTF is that hormone therapy used in postmenopausal women may lower the risk of fractures but increases the risk for stroke, blood clots, gallbladder problems, and may result in urinary incontinence. Estrogen used alone may decrease the risk of breast cancer, but combination estrogen and progestin has been found to increase the risk of breast cancer and likely dementia. (4,5)

 

Bio-identical hormones:

FDA perspective on “bio-identical” hormones: Community clinics often promote the use of hormone therapy in the form of “bio-identical hormones.” According to the U.S. Food and Drug Administration (FDA), the term “bio-identical” may be used to falsely promote hormones as safe because they are sourced from plants or identical to that produced in the human body. In fact as of 2010, the FDA stated that the term “bio-identical” was not recognized by the FDA as a medical term. Many have been persuaded by marketing to believe that phytoestrogens are different than the estrogens contained in other sources. However, the standpoint of the FDA is that regardless of where the hormones are derived, the benefits and risks are similar. FDA has approved hormone products with defined dosages which are formulated and manufactured under a high standard. The FDA has warned that “bio-identical” hormones from compounding pharmacies have a higher degree of risk because they not monitored by the FDA strictly to ensure that these formulations are safe or effective. The FDA has not approved any medication or formula containing the hormone estriol due to unknown safety or effectiveness. (6) Consumers and healthcare providers may educated by being directed to the link: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm049311.htm

 

The Endocrine Society Position Statement on Bio-identical Hormones:

The Endocrine Society has released a position statement on “bioidentical hormones,” which generally supports the statements put forth by the FDA (7). The statement may be reviewed at: https://www.endocrine.org/~/media/endosociety/Files/Advocacy%20and%20Outreach/Position%20Statements/All/BH_Position_Statement_final_10_25_06_w_Header.pdf or at www.endo-society.org

Sood, R et al tested estradiol serum levels of women taking either compounded estradiol creams or FDA approved estradiol standardized patches. It was determined that estradiol levels were significantly lower in the compounded creams compared to the patch. It was noted that progesterone serum levels were comparable in both compounded and conventional forms of oral progesterone (8).

 

Bio-identical hormones and endometrial cancer:

Three cases of endometrial cancer were reported by Eden, JA et al in women taking troches containing compounded “bio-identical” hormones. Two of the patients were taking commonly used doses of compounded estrogen, progesterone, and dehydroepiandrosterone (DHEA). The third patient was taking testosterone in addition to the other hormones mentioned. (11)

 

Progesterone vs. Synthetic Progestins:

According to Holtorf (19), women taking progesterone as part of their hormone replacement expressed a greater satisfaction than those on synthetic progestins. This author expressed that the data reviewed on women taking progesterone showed less risk of breast cancer and may avoid negative heart disease related events compared to synthetic progestins.

 

Types of estrogen recommended for patients:

Which is better, animal sources of estrogen or plant sources estrogen? Should a pill or a patch be prescribed?

 

Animal vs. plant sources of estrogen:

Smith, NL et al performed an observational study on 384 women ages 30-79 over 6 years which compared adverse outcomes during the use of conjugated horse estrogen and estradiol as part of a hormone replacement therapy regimen. It was found that conjugated horse estrogen was associated with a higher risk of venous thrombosis and a non-statistically significant greater risk of heart attack compared to estradiol. The conjugated horse estrogen did not increase the risk of stroke, but was noted to lead to higher measurements of clot promoting substances in the blood. Further research is needed to confirm these findings. (9)

If hormone therapy is prescribed, a better choice may be the use of FDA approved plant-sourced estradiol products derived from yams or soy instead of conjugated estrogens sourced from horse urine. An example of these products include the oral medication Estrace, from Bristol-Myers Squibb, Vivelle or Estraderm from Novartis Pharmaceuticals, and Climara from Berlex Laboratories. Micronized progesterone is marketed under the prescription drug named Prometrium which is synthesized from Mexican yams.

 

Should estrogen be taken by patch or a pill?:

Goodman, MP performed a review of the available research between 1990 and 2010 including comparisons between oral and transdermal estrogen delivery. The author noted the following findings to support transdermal delivery over oral pills as the superior method (13,14):

 

Dose comparison of transdermal estrogen and oral estrogen:

A daily 50 mcg transdermal estradiol patch is approximately equivalent to Premarin at a dose of 0.625 mg daily.

 

Should estrogen alone or estrogen plus progesterone be used for hormone replacement therapy?:

Estrogen plus progesterone therapy is prescribed for women with a uterus. Progesterone is used to oppose the estrogen to reduce the risk of endometrial hyperplasia and endometrial cancer. For women without a uterus, estrogen only therapy is used.

 

Starting hormone replacement therapy during menopause:

When does the benefit outweigh the risk of hormone replacement therapy?: Follow up data from the WHI trial has demonstrated that hormone therapy started in women under 60 years old and less than 10 years since menopause is useful to control vasomotor symptoms and has less risk of adverse events than when used in older women. Once over the age of 60, the risks outweigh the benefits. (2,14)

 

Length of menopausal hormone replacement therapy:

The benefits of combination estrogen and progesterone hormone therapy started early during the course of menopause or in cases of premature menopause, include a lower risk of cardiovascular disease, mortality, bone density loss, and possibly dementia. However, the risk of breast cancer increases after continuing hormone therapy after 3-5 years, and therefore it should not be used for more than up to 5 years. (14)

 

The KEEPs Study: Kronos Early Estrogen Prevention Study

This study used transdermal estrodial (Climara and other brands) which is synthesized from a chemical in yams and soy as well as micronized progesterone (marketed under the prescription drug name Prometrium) which is synthesized from Mexican yams.

The KEEPS study followed 729 women early in menopause, 45 to 54 years of age for 4 years using either placebo, 0.45 mg of low dose oral conjugated estrogen or 50 mcg of transdermal estrogen plus a cycle of progesterone each month. The study did not find any increase in risk of deep venous thrombosis, pulmonary embolism, cardiovascular disease, stroke, transient ischemic attack, breast cancer, or endometrial cancer. The hormone therapy did not significantly affect atherosclerotic change determined by measuring carotid intimal thickness. (15)

 

Weight gain and hormone replacement therapy:

Hormone replacement therapy is believed by many women to lead to weight gain. On the contrary, a study showed that less accumulation of body fat occurred during menopause in women on hormone replacement therapy for 5 years (16).

 

Educating patients on menopausal hormone replacement therapy:

U.S. Department of Health and Human Services of the National Institutes of Health produced the following information for consumers to review when deciding whether to take menopausal hormone replacement therapy. This is available at the link below. http://www.nhlbi.nih.gov/health/women/pht_facts.pdf

 

Use of androgens in hormonal therapy:

Similar to the reduction in estrogen and progesterone production seen in aging women, Haring, R et al found a progressive decline of androstenedione and testosterone levels in women as they age (25). The authors found that total testosterone decreased by 32%, the free testosterone decreased by 43%, and androstenedione decreased by 70% when comparing the 3rd to the 8th decade of life (25).

 

Testosterone use in pre and post-menopausal women:

The FDA has not approved any testosterone products for use in women, but it is used off-label in the form of creams, implanted pellets, patches, troches, injections, and is sometimes compounded by pharmacies.

 

Testosterone use in menopausal women:

 

Testosterone use in pre-menopausal women:

Currently there is no medical authority which recommends the routine use of testosterone in pre-menopausal women. Further research is needed to ensure safety and beneficial outcomes of testosterone used in this population. Testosterone therapy for 2 years without estrogen at an average dose of 121 mg in the form of an implanted pellet improved symptoms as measured by the Health Related Quality of Life Menopause Rating Scale in the majority of menopausal and pre-menopausal patients (22).

 

Testosterone safety:

Testosterone has been determined to have adverse effects of mainly the skin such as hirsuitism (undesirable hair growth in women) and acne when taken for under 6 months (20). When taken for over 6 months the long term safety is unknown. Some of the research shows positive improvements in bone mass (mild), cognitive ability, body composition, and heart disease but more research is needed (21).

 

Dehydroepiandrosterone (DHEA) use in women:

The adrenal glands use cholesterol to form DHEA in the adrenal cortex, then is converted in peripheral body tissues to produce the hormones testosterone or estrogen. DHEA is not recommended as supplement for treatment of pre or post-menopausal symptoms due to a lack of research on safety, poor efficacy, and unknown long term effects.

A 3 month, randomized double-blind placebo controlled study evaluated the use of 50 mg of DHEA or placebo taken by 60 peri-menopausal women with changes in mood and generally not feeling well. The study found that DHEA levels increased by 242%, testosterone increased by 94.8%, and cortisol decreased by 13.2% on average. It was found that HDL cholesterol decreased by 10.1% and lipoprotein A decreased by 18.1% on average but was not far different than placebo. Notable improvement was not seen by subjects taking the DHEA compared to placebo in peri-menopausal complaints such as mood, sexual function, recall, sadness, and overall wellness. (23)

In a study, DHEA products were tested for the amount of active ingredient, and out of 45 DHEA products, there was found to  be a wide variability of active DHEA present between the range of 0 to 109.5% of the stated amounts (24).

 

Androstenedione supplement use in women:

Androstenedione is produced by the ovaries and is converted in the body to both estrogen (estradiol), and testosterone. Kicman, AT et al found that a single 100 mg dose of androstenedione increased testosterone concentrations in women significantly to beyond normal range (26). The risks of both short and long term use of androstenedione by women clearly outweigh the benefits. The adverse effects of androstenedione are similar to testosterone. These adverse effects include hirsuitism (undesirable hair growth in women) and acne when taken for under 6 months (20). When taken for over 6 months the long term safety is unknown.

 

 

Assessment and Plan: Hormone Replacement Therapy in Women

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

References:

1.Women’s Health Initiative. Questions and Answers about the WHI Post-Menopausal Hormone Therapy Trials. Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute. Accessed 6/5/2014. http://www.nhlbi.nih.gov/whi/whi_faq.htm

 

2.Gurney EP, Nachtigall MJ, Nachtigall LE, Naftolin F. The Women’s Health Initiative trial and related studies: 10 years later: A clinician’s view. J Steroid Biochem Mol Biol. 2014 Jul;142C:4-11. http://www.ncbi.nlm.nih.gov/pubmed/24172877

 

3.FDA, Estrogen and Estrogen with Progestin Therapies for Postmenopausal Women. U.S. Food and Drug Administration, Page Last Updated: 06/22/2010. 10903 New Hampshire Avenue, Silver Spring, MD 20993. Ph. 1-888-INFO-FDA (1-888-463-6332). Accessed 6/5/2014. http://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm135318.htm

 

4.Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions, Topic Page. January 2013. U.S. Preventive Services Task Force. Accessed 6/5/2014. http://www.uspreventiveservicestaskforce.org/uspstf/uspspmho.htm

 

5.Nelson HD, Walker M, Zakher B, et al. Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: Systematic Review to Update the 2002 and 2005 U.S. Preventive Services Task Force Recommendations. Evidence Syntheses, No. 93. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 May. http://www.ncbi.nlm.nih.gov/books/NBK97825/

 

6.Bio-Identicals: Sorting Myths from Facts. U.S. Food and Drug Administration, Page Last Updated: 12/07/2013. 10903 New Hampshire Avenue, Silver Spring, MD 20993. Ph. 1-888-INFO-FDA (1-888-463-6332). Accessed 6/6/2014. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm049311.htm

 

7.Endocrine Society Position Statement. Bio-identical hormones. October 2006. 8401 Connecticut Ave, Suite 900, Chevy Chase, Maryland, 20815. www.endo-society.org. Accessed 6/6/2014. https://www.endocrine.org/~/media/endosociety/Files/Advocacy%20and%20Outreach/Position%20Statements/All/BH_Position_Statement_final_10_25_06_w_Header.pdf

 

8.Sood R, Warndahl RA, Schroeder DR, Singh RJ, Rhodes DJ, Wahner-Roedler D, Bahn RS, Shuster LT. Bioidentical compounded hormones: a pharmacokinetic evaluation in a randomized clinical trial. Maturitas. 2013 Apr;74(4):375-82. http://www.ncbi.nlm.nih.gov/pubmed/23384975

 

9.Smith NL, Blondon M, Wiggins KL, Harrington LB, van Hylckama Vlieg A, Floyd JS, Hwang M, Bis JC, McKnight B, Rice KM, Lumley T, Rosendaal FR, Heckbert SR, Psaty BM. Lower Risk of Cardiovascular Events in Postmenopausal Women Taking Oral Estradiol Compared With Oral Conjugated Equine Estrogens. JAMA Internal Medicine, 2013. http://www.ncbi.nlm.nih.gov/pubmed/24081194

 

10.Freeman, Sarah. Hormone therapy’s protection against endometrial cancer persists in Women’s Health Initiative follow-up study. Internal Medicine News. Oct 25, 2013.

 

11.Eden JA1, Hacker NF, Fortune M. Three cases of endometrial cancer associated with “bioidentical” hormone replacement therapy. Med J Aust. 2007 Aug 20;187(4):244-5.

http://www.ncbi.nlm.nih.gov/pubmed/17708728

 

12.Guidance for Industry Noncontraceptive Estrogen Drug Products for the Treatment of Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms — Recommended Prescribing Information for Health Care Providers and Patient Labeling 12 U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). November 2005. Labeling. Revision 4. U.S. Food and Drug Administration. 10903 New Hampshire Avenue. Silver Spring, MD 20993. Website accessed 6/6/2014. http://www.fda.gov

 

13.Goodman MP. Are all estrogens created equal? A review of oral vs. transdermal therapy.J Womens Health (Larchmt). 2012 Feb;21(2):161-9. http://www.ncbi.nlm.nih.gov/pubmed/22011208

 

14.Sood R, Faubion SS, Kuhle CL, Thielen JM, Shuster LT. Prescribing menopausal hormone therapy: an evidence-based approach. Int J Womens Health. 2014 Jan 11;6:47-57. http://www.ncbi.nlm.nih.gov/pubmed/24474847

 

15.Miller VM, Black DM, Brinton EA, Budoff MJ, Cedars MI, Hodis HN, Lobo RA, Manson JE, Merriam GR, Naftolin F, Santoro N, Taylor HS, Harman SM. Using Basic Science to Design a Clinical Trial: Baseline Characteristics of Women Enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). J Cardiovasc Transl Res. 2009 Sep;2(3):228-239. Website Accessed 6/7/2014. http://www.keepstudy.org

 

16.Jensen LB, Vestergaard P, Hermann AP, Gram J, Eiken P, Abrahamsen B, Brot C, Kolthoff N, Sørensen OH, Beck-Nielsen H, Nielsen SP, Charles P, Mosekilde L. Hormone replacement therapy dissociates fat mass and bone mass, and tends to reduce weight gain in early postmenopausal women: a randomized controlled 5-year clinical trial of the Danish Osteoporosis Prevention Study. J Bone Miner Res. 2003 Feb;18(2):333-42. http://www.ncbi.nlm.nih.gov/pubmed/12568411

 

17.Salpeter SR, Walsh JM, Greyber E, Salpeter EE. Brief report: Coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med. 2006 Apr;21(4):363-6. http://www.ncbi.nlm.nih.gov/pubmed/16686814

 

18.Salpeter SR, Walsh JM, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. J Gen Intern Med. 2004. Jul;19(7):791-804. http://www.ncbi.nlm.nih.gov/pubmed/15209595

 

19.Holtorf K. The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgrad Med. 2009 Jan;121(1):73-85. http://www.ncbi.nlm.nih.gov/pubmed/19179815

20.Braunstein, Glenn D. The Endocrine Society Clinical Practice Guideline and The North American Menopause Society Position Statement on Androgen Therapy in Women: Another One of Yogi’s Forks J Journal of Clinical Endocrinology and Metabolism. Volume 92 Issue 11 – November 1, 2007. http://www.ncbi.nlm.nih.gov/pubmed/17989127

 

21.Davis SR, Worsley R. Androgen treatment of postmenopausal women. J Steroid Biochem Mol Biol. 2014 Jul;142C:107-114. http://www.ncbi.nlm.nih.gov/pubmed/23727129

 

22.Glaser R1, York AE, Dimitrakakis C. Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS).Maturitas. 2011 Apr;68(4):355-61. http://www.ncbi.nlm.nih.gov/pubmed/21177051

 

23.Thompson RD, Carlson M, Thompson RD, Carlson M. Liquid chromatographic determination of dehydroepiandrosterone (DHEA) in dietary supplement products. J AOAC Int. 2000 Jul-Aug;83(4):847-57. http://www.ncbi.nlm.nih.gov/pubmed/10995111

 

24.Barnhart KT, Freeman E, Grisso JA, Rader DJ, Sammel M, Kapoor S, Nestler JE. The effect of dehydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and health-related quality of life. J Clin Endocrinol Metab. 1999 Nov;84(11):3896-902. http://www.ncbi.nlm.nih.gov/pubmed/10566625

 

25.Haring R, Hannemann A, John U, Radke D, Nauck M, Wallaschofski H, Owen L, Adaway J, Keevil BG, Brabant G. Age-specific reference ranges for serum testosterone and androstenedione concentrations in women measured by liquid chromatography-tandem mass spectrometry.J Clin Endocrinol Metab. 2012 Feb;97(2):408-15. http://www.ncbi.nlm.nih.gov/pubmed/22162468

 

26.Kicman AT, Bassindale T, Cowan DA, Dale S, Hutt AJ, Leeds AR. Effect of androstenedione ingestion on plasma testosterone in young women; a dietary supplement with potential health risks.Clin Chem. 2003 Jan;49(1):167-9. http://www.ncbi.nlm.nih.gov/pubmed/12507974

 

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