bhat-for-women

Bioidentical Hormone Replacement Therapy for Women (BHRT)

A (not so) funny thing happens to women as they mature.  After the biological changes of puberty, after the child bearing years, after the career is launched, the job and family fortune secured, and the promise of youth gives way to “I’ve made it,” what next?, settles in, she notices her temper becoming short, her cycles erratic, her muscles beginning to shrink, her sexual desire slackening, she tires easily, gains weight easily, especially around the middle, doesn’t sleep well, has hot flashes, night sweats, and easily becomes depressed. What is going on?

The I Ching, China’s oldest text, presents us with the perfect explanation of this phenomena.  Qi, or “life force,” describes, for women, seven (as opposed to eight for men) year cycles or patterns of evolution. (1)

  1. A woman’s Kidney energy becomes prosperous at seven years of age (1×7).
  2. Her menstruation appears as the Ren (sea of yin) channel flows and the Chong (sea of blood) channel becomes prosperous at the age of 14 (2×7).
  3. Her Kidney qi reaches a balanced state, and her teeth are completely developed at the age of 21 (3×7).
  4. Her vital energy and blood are substantial, her four limbs are strong and the body is at optimal condition at the age of 28 (4×7).
  5. Her peak condition declines gradually. The yang Ming channel is depleted, her face withers and her hair begins to fall out at the age of 35 (5×7).
  6. Her three yang channels, tai yangyang Ming and shao yang, begin to decline. Her face complexion wanes and her hair turn white at the age of 42 (6×7).
  7. The Ren and Chong channels are both declining, her menstruation ends, her physique turns old and feeble, and she can no longer conceive at the age of 49 (7×7).

Chi Po, the Yellow Emperor’s scribe, recorded the I Ching, the wisdom of the Yellow Emperor of China, circa 1070 BCE, specifically highlighted cycle 4 when the body is best developed (age 28), and cycle 5, (age 35) when the Kidney energy begins its’ decent, with thinning hair and withering teeth.

Beginning around age 35 or so, our brain, and the rest of our systems, begin to decline.  In the past, this natural “shelf life” was accepted as entirely “normal” and natural.  As we extend life towards 100 years of age and beyond, those of us in the “middle” want and need to remain vibrant, healthy and productive.

Enter Bioidentical Hormone Replacement Therapy.  Like a finely tuned, high end automobile, our body’s need certain fluids and filters to operate at maximum capacity.  Whether a Chevy or a Maserati, every model needs oil, brake fluid, transmission fluid to function optimally.  Women need certain levels of estrogen, progesterone, testosterone, DHEA, Vitamin D, adequate thyroid hormones, peak nutrients, and low levels of inflammation to function optimally.

Menopause

 (And Other Four Letter Words)

Menopause is the time of life when, due to declining ovarian function, the female sex hormones diminish.  The average age for the climacteric is 51 years old but can happen anytime between age 35 and 55.  Smokers, on average, experience menopause at an earlier age. (2)

Menopausal symptoms begin with subtle changes in the perception of body warmth followed by a sudden break into a cold sweat. (i.e. “hot flashes.”)  Other symptoms include sleep disturbances, dry skin and vaginal dryness, “brain fog,” low or absent libido, osteoporosis, headaches, anxiety and depression, weight gain, joint pain, fatigue, muscle weakness, palpitations, urinary incontinence, fibromyalgia, allergies, craving for sweets, irritability, cold extremities, scalp hair loss, swelling around the eyes and abnormal blood lipids.  All told, the Physician’s Guide to Anti-Aging and Regenerative Medicine; 2009 lists 36 separate menopausal symptoms. (2)

Clearfield Medical Group Female Bioidentical Hormone Program

Estrogen and progesterone, the main female sex hormones, rightly get the lion’s share of attention when dealing with menopause. Other hormones, specifically, the male hormone testosterone, dihydrotestosterone, melatonin, growth hormone, DHEA, insulin and pregnenolone also play a role in regulating and repairing the body’s function.

Estrogen

Estrogen engages some 400 identified functions in the body.  These include metabolic rate, improved insulin sensitivity, body temperature regulation, muscle maintenance, improved sleep, increased blood flow, decreased incidence of blood clots, decreased accumulation of arterial plaque, and preserving the amount of collagen in the skin.

Estrogen protects against heart disease, stroke, colon cancer, osteoporosis, urinary infections, Alzheimer’s disease, macular degeneration and cataracts.

Estrogen deficiency results in urinary incontinence, sagging skin and breasts, increased facial wrinkles, fatigue, depression, mood swings, and decreased libido.

In nature, Estrogen is expressed as three distinct molecules.  Estrone (E1) is the main estrogen the body produces after menopause. E1 acts as an estradiol (E2) reservoir as it converts to estrone sulfate, where it lies dormant, waiting conversion to the active estradiol (E2) when needed.  High levels of E1 may increase the risk of breast cancer.

Estradiol (E2) is the principal active estrogenic compound.  E2 acts an anti-oxidant, increasing “good” cholesterol (HDL), reducing triglycerides, LDL and total cholesterol.  It aids in memory preservation (by increasing serotonin levels in the brain), maintaining bone structure, and absorption of calcium, magnesium and zinc.

Estriol (E3), generated in the placenta, is significantly elevated during pregnancy.  E3 acts to protect against breast cancer, (3) maintains pregnancy, controls the symptoms of menopause, deceases LDL and increases HDL.  Topical E3 is used for relief of postmenopausal atrophy, vaginal dryness and urinary incontinence. It does not have the brain, bone, or heart protective effect of estradiol.

Like her male counterpart, who, 15% of the time, metabolizes testosterone into estradiol, and experiences feminizing characteristics, menopausal women can metabolize estrogen into a “good” 2 hydroxyl-form, or a “bad 16 hydroxyl form.

2 hydroxy “good estrogen” is protective against cancer.  Measuring homocysteine levels in the blood are a gauge of her ability convert exogenous estrogen, known as “methylation,” into 2 hydroxy estrone.

Exercise, cruciferous (cabbage family) vegetables, flax, soy, kudzu, rosemary, salmon, broccoli derivatives such as DIM and a Paleolithic diet, aid in conversion to the 2 hydroxy version from estrone.

SAMe, Methionine, B2, B6, B12, Folic acid (also known as folinic acid, 5-formyl THF, or 5-methyltetrahydrofolate–MTHF), and betaine also enhance one’s ability to methylate.  Stress reduction is a must.

Herbal remedies to improve estrogen balance include Bacopa Extract, Pueraria root, Red Clover, Gota Kola, Hops, Dong Quai, Black Cohosh, Schizandra fruit, Extract and Sage Leaf.

16 hydroxy “(bad)” estrone is associated with an increased risk of breast cancer.  Obesity, hypothyroidism, pesticide toxicity (organ chlorines), omega-6-fatty acid excess, and inflammatory cytokines contribute to production of 16 hydroxy estrone.

Obesity, alcohol, pesticides, estrogens in the food chain all skew the metabolism of estrogen toward the 16 hydroxy “bad estrogen.”

There is a third, minor 4 hydroxy, pathway.  4 hydroxy estrone can directly damage DNA and cause mutations enhancing tumor growth.  Synthetic estrogens, Premarin and Prempro, and uterine fibroids, increase the production of 4 hydroxy estrone.  Methionine and folic acid can reduce 4 hydroxy estrone.

Estrogen preserves brain function, protects neurotransmitters, increases nerve growth factor, and increases blood flow with resultant improved glucose and oxygen utilization and decreased beta-amyloid deposits seen in Alzheimer’s patients.

Side Effects of Estrogen: The 5 “B’s:”

Breast tenderness, bleeding, bloating, mood swings and crying (—itchyness) and break outs.

When administered without progesterone, estrogen excess promotes cyst formation in the breast (fibrocystic breast disease), uterus (fibroids), and ovaries (ovarian cysts).  Migraine headaches and gallstones are also hallmarks of excess estrogen.

An annual Pap smear, pelvic exam and mammogram are required.

Estrogen is administered orally, least preferred, as a patch, next least preferred, as a gel, or a long acting pellet.

Estrogen is typical compounded using the estradiol and estriol forms for maximum benefit.

Estriol as a vaginal suppository can be used at bedtime for vaginal dryness.

Estradiol Pellets can be implanted under the skin, along with testosterone pellets as a long acting (3 to 5 month) treatment.   Pellets are ideal for patients who travel frequently, forget to take their hormones, or have transfer issues (small children, significant others) and don’t want to risk getting the creams or gel on partners or family members.

Estrogen target blood levels are 75-100 pg/ml. (4)  Estradiol levels are best to monitor efficacy.

FSH (>50) is measured to determine menopausal state.

Wait.  What About the Elephant in the Room?  Everyone Knows Estrogen Causes Cancer: Right?(5-6)


 Don’t Hormones Cause Cancer?  Didn’t the FDA Recommend that Hormones Not Be Used?

The landmark 2002 Women’s Health Initiative study was halted early due to undeniable evidence that estrogen (Premarin) alone given to older postmenopausal patients caused a statistically significant increase in emboli and stroke.  (Of note oral estrogens caused blood clots, transdermal estradiol did not.)

Adding progesterone (Provera or Prempro) increased the incidence of breast cancer, heart attack and dementia. (7)

So Hormones Do Cause Cancer

Yes, depending on the type used, and no if placed in a proper delivery system. The study group used Premarin, conjugated equine estrogen (CEE), namely, synthetic estrogen, derived from horse urine, alone or Prempro, a combination of conjugated equine estrogen (CEE) and synthetic progestogen.

Conjugated equine estrogen (CEE) contains just 3 human estrogens out of 10 estrogenic components found in CEE.  In addition to estrone, CEE contains sodium equilin sulfate, and the concomitant components, 17 alpha-dihydroequilin, 17 alpha-estradiol, 17 beta-dihydroequilin and horse androgens and progestins. (8)

Ethinyl Estradiol, the “estrogen” in birth control pills, cannot be inactivated by normal oxidation.  It is 12,000 to 60,000 times more potent than bioidentical estradiol by weight and is trombogenic.  Oral Ethinyl Estrogen carries twice the risk of deep vein thrombophlebitis and pulmonary emboli.

Transdermal estradiol carries none of these risks.

Bioidentical or natural estrogen contains the same chemical structure as we generate at birth.  The usual source is yams.

Synthetic estrogens increase blood pressure and triglycerides.  Estrone, the cancer causing component of estrogen, causes gallstones, elevations in liver enzymes, and Sex Hormone Binding Globulin (SHBG).  Synthetic estrogen interrupts tryptophan and serotonin metabolism, resulting in brain fog, depression, increased carbohydrate cravings, lowered growth hormone and increased pro-thrombic c reactive protein, an inflammatory marker.

Natural estrogen increases endothelial nitric oxide protecting against endothelial dysfunction. (9) Natural estradiol is cardio protective, decreases the risk of acute myocardial infarction, and the risk of type 2 diabetes mellitus. (10)

Measurements of the internal carotid artery lumen are 224% wider when a patient is treated with estradiol for greater than 6 months. (11)

A study of 23, 000 women treated with (natural) Estradiol and Estriol E3 with or without progestins revealed a risk-ratio of 0.72, i.e. 28% decrease in breast cancer mortality and a risk-ratio of 0.77 (or 23% decrease) in all-cause mortality. (12-14) 

Another study involving 80,377 postmenopausal women revealed no increase or decrease in breast cancer in women on (natural estrogen) E2 and natural, (micronized) progesterone (risk-ratio 1.0).  E2 plus MPA (synthetic Progesterone) had a risk ratio of 1.69 or 69% increase in risk of breast cancer and CEE (synthetic estrogen, Premarin) alone had a risk ratio of 1.40 or 40% increase in the risk of cancer. (15)

The Notion that the Women’s Health Initiative Saved Lives by Warning Women off Estrogen is Patently False!

A 10-year randomized hormone replacement (estradiol vs. norethindrone) study after menopause revealed a significantly reduced risk of mortality, heart failure and myocardial infarction without any apparent increase in risk of cancer, venous thromboembolism or stroke in the natural (estradiol) population. (15)

A study of women treated with and without hormone replacement therapy after breast cancer revealed a 33% 10 years all mortality rate in the non-hormone users, a 12% mortality rate in non-estrogen hormone users, and a 6 % (94% survival) rate in women who were treated with natural estrogen, testosterone and natural progesterone. (16)

Women with early breast cancer should be offered hormone replacement after a full explanation of the risks and benefits. (17) 

Indeed, natural or bioidentical hormone replacement therapy, unlike Conjugated Equine Estrogen (Premarin), is safe and effective for climacteric symptoms, and as a preventative of long-term degenerative diseases including osteoporotic fractures, cardiovascular disease, diabetes mellitus, and cognitive impairment.  Non oral bioidentical estrogens do not exhibit increased incidence of venous thromboembolism (VTE) and improves blood pressure control.  Bioidentical Estrogen and (Natural Progesterone, see paper on Natural vs. Synthetic Progesterone) offer the peri and postmenopausal woman significant quality of life advantages. (18)

 

Progesterone

Progesterone deficiency manifests as anxiety, depression, irritability, insomnia, osteoporosis, hypersensitivity, nervousness, migraine headaches, weight gain, decreased libido and decreased HDL (good cholesterol).

Progesterone is secreted in the ovary.  Menopausal levels are frequently zero.  Low progesterone symptoms include excesses of stress and sugar intake, fat craving and symptoms of hypothyroidism.

Natural, as opposed to synthetic progesterone, balances estrogen, has a natural calming effect, lowers blood pressure and lowers cholesterol, is anti-inflammatory, thickens scalp hair, protects against breast cancer, coronary artery disease, osteoporosis, promotes immunity, enhances thyroid function and improves libido.

Synthetic progesterone, one of the hormones implicated in the Women’s Health Initiative 2002 report, paradoxically leads to increased appetite and weight gain, fluid retention, irritability, depression, fatigue, bloating, breast tenderness, decreased sexual desire, hair loss, insomnia, elevated “bad” cholesterol, lower “good” cholesterol and coronary artery spasm.

A delicate Estrogen/Progesterone balance exists.  Excess estrogen, either from impaired elimination, lack of physical activity, dietary deficiencies, synthetic estrogens, or production along the 16 hydroxy pathway results in agitated depression, increased risk of uterine and breast cancer, fibroids, headaches, insomnia, breast tenderness, edema and panic attacks.

Excess Progesterone results in weight gain, increased cholesterol, fatigue, depression, sugar cravings, bloating, fullness, constipation, urinary incontinence, decreased libido, breast or nipple tenderness, and immune suppression.

Progesterone is an excellent therapy for PMS, decreasing headache and bloating associated with menstruation.  It is useful for menopausal S/S and the only treatment for peri-menopause signs and symptoms.

Perhaps Progesterone’s most profound effects are its ability to reduce breast tissue proliferation. (18) Progesterone cream applied to the breast reduces proliferation. (19) Estradiol is carcinogenic in breast cell cultures unless progesterone is present. (20) Normal breast cells proliferate after estradiol treatment.  They become quiescent when progesterone is added. (21) Estradiol upregulates the cancer promoting gene bcl-2, progesterone downregulates it. (22-23

This Leads Us to The Prime Directive when Dealing with Even Bioidentical Estrogen and Progesterone:

Never, Ever, Never, Ever Use Estrogen without Progesterone

Never, Ever, Ever

And

We Insist Our Patients Pinky Swear


Testosterone (for Women?)

The director of laboratory services in a small rural hospital close to our practice called me recently wanting to know which matchbook correspondence course I got my medical license.(Literally)

“Why are you ordering testosterone levels on women,” he asked.

Similarly, at a local general medical conference, one lecture entitled “What’s New in Women’s Health Care,” the instructor, whose main point was that LDL “bad” cholesterol must be brought to 70 or less, no matter what, was asked about testosterone replacement.

“Why would I care about testosterone in women,” she replied.

As I seem to be the regional expert on the subject, all eyes turned toward me.

(As cholesterol is the prime substrate of all the sex hormones, cortisol, and aldosterone, the hormone that maintains blood pressure, hearing, sense of and balance, I find this to be a very bad idea.)

Testosterone, the male hormone, is an important component of the female hormone symphony.  Testosterone maintains bone strength, improves muscle development, energy, strength and endurance, body composition, and bone density.  It maintains skin turgor, collagen production, skin texture, sexual desire, and emotional well-being.

Testosterone decreases visceral fat, and fat deposition, cellulite and wrinkles.

Testosterone deficiency comes from menopause, adrenal fatigue (i.e. “burnout”), depression, chemotherapy, birth control pills and statins (Lipitor, Crestor, simvastatin for example, class of medications).

Lack of testosterone in women results in poor libido, inability to achieve orgasm, fatigue, weight gain, low self-esteem, muscle wasting, thinning hair and lips, anxiety, dry eyes, a pale gaunt face, thinning of the inner 1/3 of the eyebrow, and lower “good” cholesterol.

Fact:  Testosterone is Essential for Women’s Physical and Mental Health(24) 

Myth: Testosterone masculinizes females.Fact: Testosterone does not have a masculinizing effect on females.
Myth: Testosterone causes hoarseness and irreversible voice changes.Fact: There is no evidence that T causes hoarseness or irreversible vocal cord changes in women.
Myth: Testosterone causes hair loss.Fact:  T increases scalp hair growth in women
Myth: Testosterone causes liver damage.Fact: Non-oral T does not adversely affect the liver or clotting factors
Myth: Testosterone Causes Breast CancerFact:  Risk of Breast Cancer is more than double without Testosterone (25)

Testosterone replacement is done usually in the form of a transdermal gel or pellet.  Orally, testosterone is associated with liver tumors and is never prescribed.

Excess testosterone can manifest as acne across the shoulders and neck.  Testosterone overload causes facial hair, weight gain, insulin resistance, hair loss, anxiety, salt and sugar cravings, agitation and anger.

Spironolactone, an old time diuretic,and decreasing the testosterone dose, is the perfect antidote for abnormal hair growth, oily skin, agitation and acne.

Testosterone is indicated for any woman with signs and symptoms of testosterone deficiency, low testosterone levels, on estrogen or oral contraception, or one who wants to improve strength, energy, bone composition and sense of wellbeing.

Testosterone is contraindicated in pregnancy or anyone planning a pregnancy and any hormone responsive cancer.

Natural remedies for improving testosterone include exercise, getting adequate sleep, normalizing body weight, managing stress,  eating a high protein, anti-inflammatory diet, zinc supplementation, and increasing the intake of the amino acids arginine, leucine, and glutamine.

Testosterone excess is remedied with the aforementioned spironolactone, metformin and saw palmetto.

Hormones do not exist or function in isolation and we would be remiss if we did not incorporate the precursors to estrogen, progesterone and testosterone.  Review Other Hormones  to complete the Female Bioidentical Hormone Program.

Female Hormone Symptoms

Estrogen DeficiencyProgesterone DeficiencyTestosterone Deficiency
__Hot Flashes__Swollen Breasts__Fatigue, prolonged
__Night Sweats__Headaches__Memory Loss
__Apathy__Anxiety__Decreased Libido
__Brain Fog__Irritability__Muscle Weakness
__Belly Fat__Irregular Menses/Painful Menses__Palpitaions
__Bone Loss__Cramping/Swollen Lower Abdomen__Bone Loss
__Depression__Infertility__Depression
__Urinary Incontinence__Acne__Fibromyalgia
__Severe Mood Swings__Joint Pain__Brain Fog
__Vaginal Dryness__Weight Gain__Poor Motivation
__Droopy Breasts__Poor Libido__Cannot Achieve Orgasm
__Fatigue__Depression__Poor Sense of Well Being
__Poor Libido__Insomnia__Vaginal Dryness
__Hair Loss On Top of Head__Agitation/Aggressive__Aches and Pains
__Wrinkles Around Lips__”I hate my family, job, etc”__Thin Skin
__Loses Self Control
Estrogen ExcessProgesterone ExcessTestosterone Excess
__Decreased Urine Flow__Excessive Sleepiness__Acne
__Increased Urine Frequency__Mild Depression__Voice Deepening
__Poor Libido__Candida Exacerbation__Irritable/Moodiness
__Weight Gain in__GI Bloating__Loss of Scalp Hair
__Hips/Abdomen__Breast Swelling__Male Pattern Hair Growth
__Nervous/Anxious__Exacerbation of Estrogen__Clitoral Enlargement
__Irritable/Mood Swing __Deficiency__Insomnia
__Headaches__Oily Hair and Skin
__S/S Low Thyroid
__Elevated TriglyceridesCortisol DeficencyCortisol Excess
__Fluid Retention__Fatigue, On Wakening__Bone Loss
__Breast Swelling/Tenderness__Craves Sweets or Salt__Sleep Disturbance
__Craving Sweets__S/S of Low Progesterone__Poor Libido
__Fibrocystic Breasts__Allergies/Psoriasis/Eczema__Anxiety
__Uterine Fibroids__Irritablity__Depression
__Nervousness__S/S Hypothyroidism__Hair Loss
__Weight Gain__Needs Energy Drink Mid Morning__Elevated Triglycerides
__Fatigue__Needs Mid Afternoon Nap
__Heavy Menses__By Dinner Time Barely Awake
__Most Alert If Awake After 9 PM
__Nods Off Reading or Watching TV
__Low BP

References

  1. Thicken, D. “I Ching and Cycles of Jing,” Acupuncture Today, February, 2004, Vol. 5, Issue 2. http://www.acupuncturetoday.com/mpacms/at/article.php?id=28397
  2. Windham, GC, et al Cigarette smoking and effects on menstrual function. Obstetrics Gynecology, 1999;93:59-65
  3. Gordon, Mark L. Principals of Interventional Endocrinology. Physician’s Guide to Anti-Aging and Regenerative Medicine; 2009, 1 (74-75)
  4. Gordon, Mark L. Principals of Interventional Endocrinology. Physician’s Guide to Anti-Aging and Regenerative Medicine; 2009, 1 (75)
  5. Lucy the Elephant, On the Beach in Margate, New Jersey, Three towns down from Atlantic City. Built in 1881 as a Lucy the Elephant is a six-story elephant-shaped example of novelty architecture, constructed of wood and tin sheeting in 1881 by James in Margate CityAtlantic CountyNew Jersey, United States, two miles (3.2 km) south of Atlantic City, in an effort to sell real estate and attract tourists.Today, Lucy is a tourist attraction. Guided tours take visitors into the building through the spiral staircase in the left rear leg up into the interior, then up again into the howdah to see views of Margate, the Atlantic City skyline, and the Atlantic Ocean.
  6. Lucy the Elephant, On the Beach in Margate, New Jersey, Three towns down from Atlantic City. Built in 1881 as a Lucy the Elephant is a six-story elephant-shaped example of novelty architecture, constructed of wood and tin sheeting in 1881 by James in Margate CityAtlantic CountyNew Jersey, United States, two miles (3.2 km) south of Atlantic City, in an effort to sell real estate and attract tourists.Today, Lucy is a tourist attraction. Guided tours take visitors into the building through the spiral staircase in the left rear leg up into the interior, then up again into the howdah to see views of Margate, the Atlantic City skyline, and the Atlantic Ocean.
  7. https://www.nhlbi.nih.gov/whi/
  8. lef.orgjun2009, Female Hormone Restoration, Moving Forward with Bioidentical HRT
  9. lef.orgjun2009, Female Hormone Restoration, Moving Forward with Bioidentical HRT
  10. Hanaway, Patrick, Estrogen Metabolism Hormone Essentials: Presentation @A4M Lecture Series, Las Vegas, NV, December 10, 2010
  11. lef.orgjun2009, Female Hormone Restoration, Moving Forward with Bioidentical HRT
  12. Gordon, Mark L. Principals of Interventional Endocrinology. Physician’s Guide to Anti-Aging and Regenerative Medicine; 2009, 1 (115-116)
  13. Gordon, Mark L. Principals of Interventional Endocrinology. Physician’s Guide to Anti-Aging and Regenerative Medicine; 2009, 1 (125-127)
  14. Gordon, Mark L. Principals of Interventional Endocrinology. Physician’s Guide to Anti-Aging and Regenerative Medicine; 2009, 1 (125-127)
  15. http://www.wellnesshormonebalance.org/files/Female_Symptoms_List.pdf
  16. Gordon, Mark L. Principals of Interventional Endocrinology. Physician’s Guide to Anti-Aging and Regenerative Medicine; 2009, 1 (125-127)
  17. Gordon, Mark L. Principals of Interventional Endocrinology. Physician’s Guide to Anti-Aging and Regenerative Medicine; 2009, 1 (125-127)
  18. Gordon, Mark L. Principals of Interventional Endocrinology. Physician’s Guide to Anti-Aging and Regenerative Medicine; 2009, 1 (125-127)
  19. Chang KJ, Fert Steril 1995;63:785-91 BarratJ, J Gynecol Obstet Biol Reprod (Paris). 1990;19(3):269-74.
  20. Russo J, J Steroid Biochem Mol Biol. 2003 Oct;87(1):1-25
  21. Malet C, J SteroidBiochem Mol Biol. 2000 Jun;73(3-4):171-81; Foidart JM, Fert Steril,1998 May;69(5):963-9
  22. Formby B, Ann Clin Lab Sci. 1998 Nov-Dec;28(6):360-9
  23. Ordete Study: Int Journal of Cancer 112 (2004) (2), pp. 312-318.
  24. Maclaran, N. Panay, The safety of postmenopausal testosterone therapy, Womens Health, 8 (2012), pp. 263–275
  25. Glaser and Dimitrakakis. Reduced Breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: a prospective, observational study. Maturitas 2013 Dec;76(4): 342-9

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