Hormone Replacement, Contraceptive Medications, and Other Hormonal Therapies: What Do They Really Do?

Paul Reller, L.Ac.

Current approaches with contraception and hormone replacement after menopausal deficiency utilize low doses of a group of synthetic hormones called progestins, with assurances that these synthetic hormones do not have the relatively severe risks associated that the previous class of synthetic hormone therapies were proven to have. Progestins are the most frequently used form of synthetic progesterone-like chemicals, used in the OrthoEvra contraceptive patch, the DepoProvera injection, the Mirena IUD, the OrthoEvra vaginal ring, and most contraceptive and post-menopausal therapeutic drugs. Norplant was an early form of easy use progestin contraceptive that was discontinued due to numerous lawsuits claiming severe side effects of pain, weight gain, depression/anxiety disorder, etc. In 2011, a study by the University of Washington, published in the prestigious Lancet Infectious Diseases medical journal, found that use of the injected progestin contraceptive in Africa had increased the rate of incidence of acquiring an HIV infection by nearly two-fold, and the rate of passing the HIV to a partner by nearly 40 percent. This large study indicated that injected progestin contraception, such as Depo-Provera, had a significantly negative effect on the immune system. On July 9, 2002, the National Institute of Health announced that it had halted a major study of progestin estrogen combination drugs because concerns of high risks concerning invasive breast cancer, blood clots and cardiovascular disease precluded safety of the taking of these drugs in study! The NIH also found that a one year use of progestin estrogen combination increased an otherwise healthy woman's risk of heart attack by 29 percent, incidence of blood clots doubled, strokes increased by 42 percent, and breast cancer incidence increased by 29 percent. On May 30, 2003, further reports published in the Journal of the American Medical Association showed added risks of developing neurodegenerative conditions such as dementia, with a 105 percent increase in risk, as well as a 33 percent increase in hip fracture incidence, 37 percent increase in colon cancer incidence, and 111 percent increase in the risk of blood clots. A large multicenter study of the newer types of progestin plus estradiol was initiated by the FDA and this report was released in 2011, showing a 55-74 percent relative increase in the incidence of both arterial and veinous thromboses and embolisms with the use of the newer forms of oral contraceptive tablet, injection, and vaginal ring (see the study results in more detail below). The U.S. CDC (Centers for Disease Control and Prevention) lists a 5 year use of contraceptive synthetic hormones as one of the most significant risks for acquiring cervical cancer, most of which is assciated with a viral infection.

Also in 2011, a selective study of the broad Women’s Health Initiative study sponsored by the National Institutes of Health, was published in the Journal of the American Medical Association, asserting that data from this large study indicated that for a select group of patients, those that had undergone hysterectomy (surgical removal of the uterus), hormone replacement therapy using unopposed estrogen had resulted in decreased cardiovascular and cancer risks. Most of the women in the WHI study had been taking a combination of estrogens with progestins. A specific group had been given unopposed estrogen. Follow-up study by the WHI found that those women who had been taking unopposed estrogen after a hysterectomy had a 23 percent lower incidence of breast cancer, instead of the markedly higher incidence of breast cancer in the group taking a combination of progestins and estrogens. The point that was not emphasized in the JAMA article, though, was that these women had been prescribed estrone, a natural bioidentical type of estrogen derived from the urine of pregnant horses (e.g. Premarin). Estrone is one of three known types of human estrogen, and differs in effect from estradiol, or estriol. Estrone primarily provides a precursor bioavailability to local production of estradiol. Estradiol sulphate, and other synthetic estradiols commonly used in hormone therapies did not produce a decrease in breast cancer risk in this group of post-hysterectomy patients. While a number of studies over the years have demonstrated that estrone presents less risk in hormone replacement than synthetic estradiol, there still persists an economic need to promote the more profitable prescription of synthetic estradiols, and combinations of synthetic estradiols and progestins. News articles and journal headlines concerning this study inaccurately give the impression that the study results imply that perhaps a combination of progestins and synthetic estradiol may not increase risk of cardiovascular disease and cancer.

This WHI study also revealed that this subset of women, namely those that received a hysterectomy in their 50s and were placed on estrone (not synthetic estradiol) therapy, had no increased incidence or risk of cardiovascular disease, hip fracture, colon cancer, or premature death. The study did reveal, though, that women placed on unopposed estrogen therapy, or continued with unopposed estrogens later in life did have a markedly higher incidence risk in these categories. Experts at the Women’s Health Initiative (WHI), such as Dr. JoAnn Manson, of the Brigham and Womens Hospital in Boston, stated that these findings did not mean that more women should be placed on unopposed estrogen earlier in life, but that instead, these findings should be used to explore why breast cancer risks were decreased with the use of estrone (not synthetic estradiol) at this age. The medical extrapolations associated with this new evidence did not reflect the details of this study, but like so many examples of evidence-based practice today, merely changed clinical guidelines based on a short summary of the WHI study. The response to this assessment in gynecology was a push for the use of ‘unopposed estradiol’ in the form of etonogestrel plus ethinyl estradiol in the NuvaRing and subdermal implant as the preferred contraceptive for premenopausal women. These now popularly prescribed hormonal contraceptives are not actually unopposed estradiol, though, but a combination of the third generation of progestins plus synthethic estradiol. An obvious assumption would be that the synthetic estradiol and progestins exerted significant risks of cancers, cardiovascular disease, and osteoporosis, for all women, while the use of natural estrogens did not, but the medical field obstinately failed to distinguish the details of this scientific evidence. Of course, there is no current practice of the use of bioidentical hormone therapies for contraception. Once again, the wording of the study summaries, not distinguishing between synthetic estrogens and natural estrogens, results in a failure to grasp the consequences and risks. This array of confusing and often seemingly contradictory evidence and advice has served to put off women to gaining a real understanding of this subject of significant risk and harm from synthetic hormone replacement and contraception. Some understanding of the steroid hormones in our bodies is necessary to fully grasp the fundamental facts concerning healthy hormonal balance and the ramifications of altering this balance. Without a basic understanding, an intelligent proactive participation in decisions regarding hormonal therapies, either contraceptive, post-hysterectomy, or post-menopausal, is difficult for the patient.

Cardiovascular risks in the modern contraceptives, and the realistic picture of overall health risks, common and uncommon side effects

In 2011, the U.S. FDA updated its risk of cardiovascular adverse effects for the new generation of supposedly safer oral, transdermal and localized contraceptives twice, notifying healthcare professionals that the final report of an FDA-funded study of contraceptives containing the progestin Drospirenone (Yaz, Yasmin et al), as well as the other marketed new generation of “safer” contraceptives, revealed a 75 percent increase in risks of blood clots (thromboses and embolisms that lead to heart attack and stroke). The principle investigators on the study included prominent MD researchers from the University of Washington (Dr. Fred Connell) and Vanderbilt University (Dr. William O. Coopper), as well as lead researchers and pharmaceutical analysts from Kaiser Permanente. These investigators stated that there has been a long and considerable concern about the risks of cardiovascular consequences in both arterial and veinous health from combined estradiol and progestins in large part due to the prothrombotic effects of synthetic estradiols, but insufficient data from a lack of scientific study of the long-term effects of the drospirenone plus ethinyl estradiol tablet (DRSP - e.g. Yasmin or Yaz), norelgestromin plus ethinyl estradiol transdermal patch (NGMN - e.g. Ortho Evra), and the etonogestrel plus estradiol vaginal ring (ETON - e.g. NuvaRing). This study included 835,826 women with 898,251 person-years of use of these contraceptives, and can be considered highly accurate and predictive of risk. Significantly higher risk of venous thromboses and embolisms (VTE) were associated with these newer contraceptives than the prior low-estradiol oral contraceptives, with relative risks of 1.55 to 1.74. Relative risk is the risk of an event or disease occurrence due to exposure, and is a ration of probability of the event or disease occurring versus a non-exposed group. The increased risk of incidence of veinous thromboses and embolisms is thus 55-74 percent increased with this type of contraceptive use. The drospirenone plus ethinyl estradiol tablet was associated with significantly higher risk of both arterial thromboses and embolism, and veinous thromboses and embolism, and was associated with this higher risk with less than 3 months of use, whereas the other contraceptives studied were associated with the increased risks after one year of use. With the use of this tablet, the risk for veinous thromboses and embolism was significant in the 10-34 year age group. These are the definitive findings of a very conservative, multicentered, long-term, and very large scientific study.

The large multicentered study found that, contrary to marketing, the NuvaRing, or vaginal ring with the combined chemicals, had a very significantly higher risk of veinous thromboses and embolisms compared to the standard contraceptives used in prior years. New reports of this study have only emphasized the contraceptive hormone tablets, Yaz or Yasmin, diverting attention from the more popularly prescribed NuvaRing. The NuvaRing website itself lists blood clots, strokes, heart attacks, hypertension, heart disease, cancers of the breast, uterus and ovaries, gallbladder disease, liver tumors, triglyceride elevations, and pancreatitis as significant risks, and side effects commonly reported of increased incidence of vaginal infections (e.g. yeast infections), and weight gain, with less commonly reported side effects of headache, irregular menstrual bleeding, changes in the menstrual cycle, temporary infertility after stopping the contraceptive use, swelling and edema, darkening of the skin, weight changes, depression, nervousness, dizziness and hair loss. While depression and anxiety (nervousness) are de-emphasized in this warning by the company, most women that have used contraceptive hormones are fully aware of the often immediate disturbing emotional lability, anxiety and depression that occurs with these drugs. A large percentage of women discontinue use due to the severity of these psychological side effects, and many prescribing doctors change the prescriptions to variations on the hormonal contraceptive chemicals until these psychological side effects are decreased. The February 7, 2011 Product Mongraph of NuvaRing from the manufacturer Merck Canada Inc., stated that: “Patients with a history of emotional disturbances, especially the depressive type, may be more prone to have a recurrence of depression while using combination hormonal contraceptives (including Nuvaring). In cases of serious recurrence, a trial of an alternate method of contraception should be made which may help to clarify the possible relationship. Women with a premenstrual syndrome (PMS) may have a varied response to combination hormonal contraceptives, ranging from symptomatic improvement to worsening of the condition.”

The researchers of this FDA sponsored definitive study of modern popularly prescribed hormonal contraceptives concluded: “The main findings of this study are that all use of the drospirenone plus ethinyl estradiol pill (Yaz or Yasmin) and each of the continuous exposure preparations, the norelgestromin plus ethinyl estradiol transdermal patch (Ortho Evra) and the etonogestrel plus estradiol vaginal ring (NuvaRing), are associated with an increased risk of veinous thromboses and embolisms relative to the standard low-dose oral contraceptive pills.” The authors also stated: “The Medicaid site population was considerably younger than the KP sites and had higher rates of comorbidities (not shown).” This particular study addresses just one of the list of risks for these synthetic hormonal contraceptives, and does not imply that the other risks are unimportant or insignificant. Veinous thromboembolisms present a very underdiagnosed medical condition that leads to a variety of health problems, including a pulmonary embolism which may result in death, a heart attack, leg pain or swelling, chest pain, heart palpitations, anxiety, shortness of breath, and osteonecrosis. Standard medical websites addressing veinous thromboembolism do not emphasize hormonal contraceptives as a risk factor for veinous thromboembolisms. The standard risk factors include obesity, varicose veins, inflammatory bowel disease, surgery, trauma, immobility, cancer, prior stroke, and aging. Patients with these risk factors should be more concerned with the use of synthetic hormonal therapies.

The vaginal ring (OrthoEvra) may also be associated with a higher risk of cervical cancer, given that the use of the combination progestin and synthetic estradiol is associated with an increased risk of viral infections such as HIV in large studies, and that the vaginal ring also has a risk of irritation of the vaginal membrane, vaginitis, and increased incidence of yeast infections, all of which increase the risk of the human papilloma virus (HPV) types that are associated with most cervical cancers to infect and spread. Added to this is the finding by the manufacturer that the vaginal ring is associated with a higher risk of uterine cancer. Since Merck is the manufacturer of both the popular OrthoEvra vaginal ring contraceptive and the most popularly prescribed HPV vaccine, Gardasil, there is an obvious reason why Merck is investing so heavily into lobbying to mandate the HPV vaccines in prepuberty, which may alleviate future concerns about the OrthoEvra vaginal ring and the increased risk of cervical cancer. But the question of the HPV vaccine has not addressed the effectivenss, or the risk-versus-benefit, of this vaccine. In 2009, Dr. Diane Harper, a lead researcher for Merck who helped design the phase 2 and 3 trials of Gardasil, questioned the efficacy of this vaccine (see the link to the CBS investigative report below). Dr. Harper stated that data showed that the vaccine lasted a mere 5 years, with no data to support its effectiveness after this time period. Dr. Harper stated: “If we vaccinate 11 year olds and the protection doesn’t last...we’ve put them at harm from side effects, small but real, for no benefit. The benefit to the public health is nothing, there is no reduction in cervical cancers, they are just postponed, unless the protection lasts for 15 years, and over 70 percent of all sexually active females of all ages are vaccinated (to significantly stop the spread of the HPV strains that cause cancer).” Dr. Harper also stated that the risks of serious adverse events after taking the HPV vaccine is comparable to the rate of serious cases of cervical cancer in the population, and that she believes that these risks with the vaccine are underreported, as they are based statistically on the denominator of doses distributed from Merck’s warehouse, not the number of doses taken by the patients. Dr. Harper also stated that she believes that the aggressive marketing by Merck may be giving women a false sense of security, undermining sensible measures that can be taken by women to decrease the risk of HPV and of cervical and uterine cancers (see the article entitle Cancer on this website).

Understanding natural and synthetic steroid hormones

Progestins are considered a class of steroid hormones in the body that includes progesterone, which is the most biologically active progestin in human metabolism. Natural progesterone is synthesized in the body from the precursor pregnenelone, which also is the precursor to DHEA (dehydroepiandosterone), which is the precursor to both estrone and testosterone. Estradiol, the most biologically active of the estrogens, many be synthesized in the body from testosterone or estrone. There are many pathways of steroid hormone production in the body, though, both systemic, glandular, and local, and a complex system of feedback regulation keeps the circulating and local levels optimum for effective metabolic regulation. Estrogen receptors may be stimulated by a variety of chemicals, especially estradiol, estrone and estriol, with estradiol exerting the most effect. In local tissues, such as the breast tissue, estrogen receptors may be stimulated by estradiol created from local testosterone or estrone. Circulating estradiol may not be as important as the production of localized estradiol in these tissues concerning cancer stimulation. Imbalances of precursor hormones, or the rate of conversion of hormones in breast tissues via aromitization, may be more important to the question of breast cancer risk than the level of circulating estradiol. Synthetic estradiol as a hormone replacement thus may have negative consequences on breast cancer risk, whereas maintenance of a hormonal balance and natural ability to regulate steroid hormones will have a positive protective effect.

Estriol is the most abundant of known forms of estrogen in the human body, and is especially abundant during pregnancy, as it is converted from DHEAS in the placenta. The human placenta produces much pregnenelone and progesterone from circulating cholesterol. The adrenal tissues of the fetus convert pregenelone to DHEA, which becomes DHEAS, and the DHEAS is converted in the liver of the fetus to a form that converts to estriol. Estriol is also produced in the adult ovary. Estriol was first isolated in 1930, from study of human pregnancy urine metabolites and placenta, and was found to convert to estrone in the human body. Subsequently, a plant source of bioidentical estriol was found to be derived from the Pussy Willow. Dr. John R. Lee, a pioneering M.D. researched such data to create bioidentical hormone therapies that were safe and effective, and widely used today as topical creams. Estriol has been periodically researched as a form of estrogen that exerts estrogen-like effects, stimulates increased production of estrone, and offers a protective effect against estradiol dominance and its cancer risks. The use of bioidentical hormone therapies has been fiercely fought since these studies in the 1930s revealed the potentially safe and effective use of such therapies, and medical industry journals have been loathe to publish any studies concerning estriol or bioidentical hormonal therapies.

In studies of women who are not pregnant, the blood production rate of estriol was measured and found to be significantly higher in the luteal phase of the menstrual cycle (second half of the cycle). The metabolic clearance rates were the same for estriol in circulation during the follicular and luteal phases of the cycle (see study cited below in information resources). There is little data on estriol values in non-pregnant women before 1999, mainly because estriol was considered a weak estrogen compared to estrone and estradiol. In 1999, a small study was finally conducted to determine the estriol production in the non-pregnant female at the Tahoma Clinic in Kent, Washington, and these researchers found that estriol was the most abundant estrogen of the three known estrogens, estriol, estrone, and estradiol, in the non-pregnant woman, and much less fluctuating than these other estrogen forms (Altern Med Rev. 1999 Aug(4):266-70). A subsequent study by Morris R. in 1981 (cited below) showed that estriol values in a non-pregnant woman, measured by radioimmunoassay of the urine, measured as 80% of total estrogens. Despite these studies, many standard experts still insist to patients that estriol is probably not abundant in the non-pregnant woman based on the early study of estriol in pregnancy. Each attempt by researchers to suggest that estriol is a viable and safe hormonal therapy over the decades has been dismissed as standard medicine has pushed the widespread use of the patented synthetic estradiol chemicals. Estrone itself was ridiculed for years until popular demand created the need for this safer estrogen therapy in the form of Premarin.

In the 21st century, most women are now realizing that it is vital that each individual woman takes a proactive approach to understand their hormonal physiology and make correct decisions concerning risks of hormonal therapies and ways to maintain the healthiest hormonal balance. Standard medicine has not provided a reassuring approach to women’s health, and the results of these standard approaches over the last half century and more are alarming. Relying on the pharmaceutical industry to provide guidelines in women’s health has been devastating, as revealed by the large Women’s Health Initiative study of 1999. Not only the alarming prescription history of synthetic hormones despite the evidence and clinical incidence of serious long term side effects and health risks, but the alarming rates of surgical removal of the uterus, ovaries and breasts in the U.S. compared to Canada, Europe and other developed nations has finally created much concern in the female population in the United States. The uterine and ovarian tissues continue to produce steroid hormones after menopause, and removal of these organs creates a need for either increased production of steroid hormones in other tissues, or the use of synthetic hormone replacement therapy. In other words, medical guidelines that support increased rates of hysterectomies produce increased prescription of synthetic hormone replacement therapy. The difference in recent years between the hysterectomy rates in the U.S. and Canada are striking. Between 2000 and 2010, the rate of hysterectomy in Canada decreased to 338 per 100,000, while the rate of hysterectomy increased in the U.S. population to the point where 1/3 of women could expect to have a hysterectomy by the age of 60. In the United Kingdom, 1/5 of women were likely to have a hysterectomy by this age. In Canada, approximately 23,000 hysterectomies were performed per year in recent years, whereas in the U.S., 617,000 hysterectomies were performed in 2004, with the rate of hysterectomy increasing yearly. The rate of hysterectomies is approximately 3 times higher in the U.S. than Canada.

In 2002, The U.S. Centers for Disease Control (CDC) stated that hysterectomy was the second most frequently performed surgical procedure in the United States, after cesarean section, for women of reproductive age, with approximately 20 million U.S. women having had a hysterectomy. By 2010, this number had increased to the point where approximately one third of women of post-menopausal status have had a hysterectomy. Some studies have indicated that we are approaching a point where approximately 60% of women at age 65 will undergo a hysterectomy. The majority of hysterectomies were performed among women earlier than the age of 44, and the highest rate of hysterectomies occurred in the 40-44 age group (11.7%, with 16.8% in the black population). Hormonal imbalance, which is the main driver of uterine fibroids, endometriosis, and uterine prolapse, was the main cause for these hysterectomies. The post-menopausal group had the second highest rate of hysterectomies, and again, hormonal imbalance was the main driver of the cancers, hyperplasias, and prolapses that were cited as the reason for choosing a hysterectomy. In addition, a majority of patients undergoing hysterectomy had a bilateral surgical removal of the ovaries. To understand endometriosis, uterine fibroid, and ovarian cyst pathology better, you may go to the article on this website addressing these concerns. Better hormonal balance, health maintenance, and preventive medicine with the integration of Complementary Medicine could reduce the incidence of hormonal symptoms, unnecessary surgical removal of sexual reproductive organs, and the high rates of cardiovascular disease, cancers, osteoporosis, and neurodegenerative disorders in the aging female population.

Besides the alarming lack of professional guidance concerning the actual long term risks of synthetic hormone replacement and contraceptive hormonal therapies, we are now finding out that standard medicine has promoted much misinformation to guide choices in women’s health. Women are routinely told that the ovaries and uterus cease to function after the reproductive years, and thus there is no reason to avoid surgical removal of these organs, especially as hysterectomy and ovarian removal, and even removal to the breasts, could reduce the risk of cancers. This is not true. As early as 1965, studies showed that postmenopausal ovaries frequently maintained a steroid hormone production capability for several decades (Novak et al, Am J Obs Gyn 93:669 1965). There is a marked change in the type of hormonal production in these tissues following menopause or hysterectomy, but nevertheless, they do still contribute to hormonal production and balance. Aging ovaries actively produce androstenedione, a precursor to estrone. By urging many women in the United States to have unnecessary removal of the ovaries, uterus, and even breast tissues, and now to unecessarily urge many younger women to utilize progestin therapy in IUDs, inserts, or orally, that stop ovulation and menstruation, standard medicine has reduced the capacity for millions of women to maintain a normal healthy hormonal homeostasis. Sides have clearly been drawn in this area of women’s health, and standard medicine has decided that synthetic hormone therapies are the crux of their business, and that the subject of natural hormone therapies and homeostasis is a threat to their business. Still, a growing body of medical doctors, inspired by Dr. John R. Lee, and subsequent MDs, are now promoting natural estrogen therapies and Complementary Medicine in the arena of gynecology. An even greater number of women are taking control of their reproductive and hormonal health and seeking to proactively understand and participate in achieving better hormonal health with Complementary Medicine.

Today, the subject of natural estrogens is a complicated subject. Women are realizing that the term estrogen does not apply to just one chemical. Besides the three most abundant estrogens in our bodies, estriol, estrone and estradiol, a number of chemicals in foods and even industrial chemicals are now called estrogens or estrogenic. Phytoestrogens, or chemicals in plants and foods that are similar to human estrogens, exert some mild estrogen-like effects in the body, but do not directly stimulate human estrogen receptors like human estrogens. Estriol derived from the Pussy Willow appears to be the exception to this rule, but estriol does not exert a strong estrogen stimulation at most estrogen receptors, and appears to work mainly by creating a more abundant bioavailability for estrone and thus estradiol, as the body needs these more potent hormonal chemicals. Laboratory analysis shows that in the estradiol deficient female, a small dose of topical estriol cream will stimulate increased production of estradiol. Since estradiol may be produced in local tissues from testosterone, though, overall hormonal balance, and adrenal health, are also very important to estradiol physiology and estrogen receptor effects.

Isoflavones, such as those found in the soy bean, exert estrogen effects that stimulate increased estrogen-mediated metabolic effects. Thus, in some women, these plant phytoestrogens, or isoflavones, are able to modulate estrogen effects and calm some symptoms of estrogen imbalance, such as menopausal or post-menopausal hot flush. Phytoestrogens are also found to be potent estrogenic chemicals, able to stimulate increased estrogen production. Environmental, or industrial xenotoxic estrogens, are increasingly abundant in our world, and are shown to have a potential for blocking estrogen receptor activity, thus causing negative effects. Phytoestrogens, on the other hand, have been shown to have little or no antiestrogeic activity. The metabolism and physiology of estrogen feedback and production, and estrogen receptor activities, is complex and fluid, though, and the research of various estrogen-like nutrients, and estrogen-stimulating hormones, such as enterolactone, has produced a complex set of research findings. Human clinical trials have demonstrated that various isoflavones and coumarins, and lignan stimulation of enterolactone, have produced a variety of positive effects on estrogen receptor modulation, though, and do have a significant role in modulating symptoms of steroid hormone imbalance and deficiency, and in decreasing risks for estrogen receptor positive cancers. Studies in 2003 demonstrated that various phytoestrogens bind to different estrogen receptor types with different affinities and that the potential to increase the rate of estrogen receptor binding to a estrogen response element also varies between phytoestrogens.

Hormones act on the body's tissues by stimulating a wide variety of metabolic actions. Hormones themselves do not affect these cellular actions, but are a type of molecule that attracts to receptors that stimulate the activities. Steroid hormones are very similar to one another, and consequently may easily convert to other steroid hormone forms in the body as needed. This feedback system of hormonal balance is called the endocrine system. The term endocrine literally means to secrete within, and comes from the roots endo- meaning absorbing within, and -krino, to separate. When the hormones are synthetically altered, forms are found that may stimulate certain processes or receptors, but will not stimulate all of the metabolic effects of the natural hormone, and will not be able to convert to other forms of steroid hormones as needed. Symptom relief and contraception are achieved, but the inhibition of the sum total of healthy hormonal effects and regulation are eventually a major health concern.

Synthetic progestins are a group of altered progesterone hormones that still act upon progesterone receptors, but do not stimulate all of the hormonal effects that natural progesterone does. The first progestin synthesized was a derivative of pregnenelone, not progesterone. Many scientists now are of the opinion that the synthetic progestins we use in therapy are not actually progesterones, but more related to androgens. With the use of synthetic progestins the menstrual cycle may be disrupted and the woman may not only prevent pregnancy, but often will have the menstrual cycle itself discontinued. While elimination of the monthly bleeding cycle may be convenient as far as the lack of need to use menstrual products, the menstruating woman obtains most of her normal progesterone and estrogens from the normal menstrual cycle, and continued disruption will have long term consequences of hormonal deficiency that will not completely be addressed with the continued use of the synthetic or combination drugs. The long term use of even low dose synthetic steroid hormones increases risks of common health problems because they result in less production of natural hormones in the endocrine feedback system. The risks of hormonal imbalance affecting a variety of systems, especially inflammatory regulation and tissue repair and maintenance, increase over time. If one chooses to take synthetic hormones, which is a relatively safe therapy for a percentage of women, it is advisable to address these issues of potential risk and side effects by seeking care from an knowledgable Complementary Medicine physician, both as a preventative medicine, or to treat the side effects and risks as they develop.

Another response to the risks and side effects of standard hormonal therapies in medical practice has been the reintroduction of topical synthetic hormones. In 2002 estrogen creams were reintroduced to the standard practice in response to the public alarm over current hormonal replacement therapies, as well as to respond to the growing interest in topical creams that utilized herbal bioidentical hormones. There was unfortunately an alarm sounded in the industry over reports of these synthetic hormones affecting children, causing such symptoms as breast enlargement and early puberty. In 2007, the use of topical synthetic hormones was again reintroduced, this time as a spray utilizing low dosage synthetic estradiol on the inside of the forearm. Unfortunately, once again, on July 29, 2010, the FDA had to issue a safety warning that the use of the topical synthetic estradiol spray, Evamist, appeared to adversely affect children and pets that came into contact with the skin of the patient using the drug, causing breast enlargement and nipple swelling in small children, both male and female, and swelling of the vaginal tissues in small children (see the link to the FDA warning below). The report indicated that these adverse effects were consistent with premature puberty in females and male gynecomastia, which are conditions that are seen with increasing frequency in the U.S. population today. There has also been concern raised over the slow breakdown of these drugs outside of the body and their introduction into the water supply by bathing as well as urinary excretion and dumping of unused pills into waste. There are few measures taken by common water treatment plants to address these chemicals in the public water system, and areas of the country that depend upon water from the underground aquifers are most affected.

Synthetic hormones are primarily used because the pharmaceutical industry is able to patent them and thus control profits. Natural, or bioidentical hormones, are simple chemicals that are found in identical forms in both plants and animals. Synthetic hormones create numerous eventual side effects by a variety of metabolic routes, not only stimulating unwanted actions within the body, but also creating a cascade of events by not stimulating metabolic actions while creating a feedback mechanism that prevents normal production of the analogous hormones, as well as eventual deficiencies of similar steroid hormones that depend on the balanced endocrine feedback system to control levels. These other steroid hormones include insulin, as well as the estrogen, androgens, pituitary hormones etc., and hormonal imbalances may affect a wide variety of hormones, including thyroid hormones, parathyroid hormones, adiponectin, ghrelin, Vitamin D3 hormone, and others.

Research in recent years (cited below in information resources) has discovered that women with metabolic syndrome (diabetes type 2), and insulin resistance, should perhaps avoid the use of estrogen replacement with synthetic progestins. This is because the progestins are found to interfere with the cellular hormone adiponectin, and may significantly decrease the release of adiponectin into circulation, thus both upsetting normal balance of inflammatory mediators, and decreasing the body's protection against buildup of atherosclerotic plaque. Progestins have been found to promote atherosclerotic plaque and instability of this plaque, leading to increased risk of thromboemboli, the main cause of strokes. Synthetic estradiol, and relative estradiol dominance, have also been associated directly with metabolic syndrome and insulin resistance, especially with women that experience increased midsection fat (android obesity). Since the problem of metabolic syndrome (see related article on this website) is becoming increasingly prevalent, these cautions and warnings affect a large number of patients that may want to utilize synthetic hormonal birth control or menopausal medicine.

The choices that women now have include the simple solution with synthetic hormone replacement, which comes with an eventual complicated set of potential risks and an array of health problems in your future, or a more complicated attention to the maintenance of healthy physiological function and processes with an holistic health regimen now, and a healthy life and function in the future. The holistic regimen utilizes professional guidance from a Complementary Medicine physician that integrates with your M.D. gynecologist and utilizes an array of treatment options that includes bioidentical hormones, herbal formulas, acupuncture and nutrient medicine, as well as the expert knowledge to help you understand fully your own health and healthy physiology. The proactive approach is more complicated than taking a single pill, but the rewards are great. Many women are frustrated by the array of information and lack of success when attempting this process without professional guidance. Poor quality products and information provided to sell these products rather than to simplify your understanding are the main stumbling blocks. Professional products and guidance assures greater success.

The following is a list of prior and current common forms of hormonal replacements and contraceptive chemicals that were studied for over fifty years and resulted in stern warnings concerning long term use:

• Estradiol benzoate: estradiol benzoate is given in 3 drug forms: estradiol, and with testosterone and progesterone synthetic medications. The FDA warns that estrogens increase the risk of endometrial cancer, heart attack, stroke, breast cancer, pulmonary emboli and deep vein thrombosis. The studies confirming this risk dealt with synthetic estrogens.
• Estradiol ethinyl and mestranol: these common birth control synthetic estrogens are nearly identical and cause the same side effects. Currently, side effects and risks are theoretically reduced to acceptable levels by prescribing extra low dosage. Birth control regimens often use monophasic regimens for ease of use, where the type of pill dosage is not varied over the cycle. Bi- and triphasic pill combinations seek to more closely mimic natural cycles with varied dosage of hormones, but the prescribed hormones are still always at higher levels than normal menstrual cycle natural hormones. The phased pill regimens sometimes use dummy pills for up to seven days in the regimen to give the woman a break from the synthetic hormone dosage.
• Progestins in birth control; eight forms: levonorgestrel, norgestrel, ethynodionol diacetate, norethindrone acetate, northendrone, norgestimate, desogestrel, gestodene: The prescribing doctor will often have to try more than one type of progestin to reduce immediate side effects. The patient often is poorly informed concerning the greater risk of the long term side effects that are more important, and assumes that decrease in immediate side effects prevents the long term consequences. Patients are also told that low dosage will prevent long term consequences, which is a subject facing strong debate among researchers. Extra-low dosage comes with less effective birth control statistics, but health care providers consider these acceptable. Localized delivery of a low dose of progestins via the IUD is now often prescribed as a contraceptive. The progestins in this device do exert the same systemic effects on the endocrine system as topical and oral progestins. This is evident by the fact that for a high percentage of women using this IUD with progestins, ovulation and the menstrual period itself is stopped.
• A high dose injected progestin contraceptive, such as Depo-Provera, or depot medroxyprogesterone acetate, is now the most popular hormonal contraceptive in the world, since it needs only one injection every 3 months. In 2011, a large study following nearly 4000 African women and their sexual partners found that use of this high-dose progestin nearly doubled the rate of acquiring an HIV infection in a country with a high rate of such infections. The study uniquely followed the sexual partners of the women, and found that when a woman was infected with HIV that those who used the high-dose injectable progestin passed this infection on at a rate nearly 40% higher than those not using the contraceptive. The WHO is following up on this University of Washington study to see if new international guidelines should be written. The implications are that a high dose progestin may not only affect the hypothalamus, GnRH, FSH, LH, and estradiol levels, but may significantly decrease the immune function in specific ways. We already were aware that use of this high dose progestin affected the cervial mucus and caused the endometrial membrane to become thin and atrophy, as well potentially causing bone loss. Some studies showed that the synthetic hormone affected the vaginal tissue as well, and there is speculation that progestin causes immunological changes in the tissues of the vagina and cervix. Measurements showed that increased numbers of HIV in genital fluids were found in women using the injected high dose progestin, as well, though, indicating that a more generalized affect on the immune system might be caused by the synthetic hormone. The researchers tracked the use of condoms and eliminated this as an explanation. The links between the endocrine and immune systems do appear stronger as more and more research uncovers the ways that immune cytokines and hormones interact at cell receptors.
• Progestin derivatives in post-menopausal hormone replacement; seven forms: allylestenol, norethisterone, danazol, dydrogesterone, medroxiprogesterone acetate, cyproterone acetate, and tamoxifen: Progestins are now considered a more acceptable form or synthetic progesterone in post-menopausal regimes because low dosage purportedly protects the woman from the cancer causing tissue stimulation of the synthetic estrogens. Studies have revealed that most of these progestins have little or no inhibitory effect on suppression of endometrial hyperplasia caused by the usual prescription of the least risky conjugated equine estrogen in these pills. Today, there are many combination drugs that include tamoxifen, including cancer drugs, acne drugs, . In the U.S. tamoxifen is prescribed for 5 years for postmenopausal women with hormone-receptor positive localized cancerous or precancerous lesions as a precaution. The usefulness of this long prescription of a progestin has been highly questioned in Europe since 2003, due to studies noting long-term side effects and limited effects on the time of recurrence of precancerous or cancerous lesions. Standard protocol reduced the time of use to 18 months for most women in Europe, and many European medical doctors switched to a protocol using only aromatase inhibitors, which were shown to have fewer side effects and thus fewer withdrawals from treatment (The Lancet, Vol.365;Issue 9453, Jan2005). A number of studies now show that concurrent use of an antidepressant SSRI significantly decreases Tamoxifen efficacy, opening a broad arena of questions concerning hormonal therapy with progestins and concurrent prescription of these antidepressants.
• Estradiol: there are 124 brand names for estradiol delivered by itself, including Vagifem, Encore, Estrace, Femestrol, Menorest, Ovocyclin, and Syndiol.
• Estradiol combination drugs: there are 24 brand name mixtures containing estradiol benzoate, including Triphasil, Alesse, Tri-Cyclen Lo, and Brevicon. Often, the patient does not realize that they are taking estradiol benzoate. Yasmin, or Yaz, is a combination of estradiol ethinyl and drospirenone, a synthetic progestin, and is a widely prescribed oral contraceptive. Estradiol ethinyl is now the most prescribed form of synthetic estradiol or contraception, due to the slower breakdown in the liver, and increased reliability as a contraceptive. It was the first semisynthetic oral estrogen prescribed, but lost FDA approval in 2004 in the form of Estinyl.
• Effects of estradiol benzoate: studies confirm that estradiol benzoate (EB) stimulates a dopaminergic mechanism in the brain. Dopamine is the main inhibitory neurotransmitter in the central nervous system, and is the target of many anti-depressants and anti-anxiety medications. EB is shown to inhibit prolactin release, and this mechanism is now linked to many psychological disorders, including depression and schizophrenia. This mechanism is normally blocked by increased noradrenergic activity, meaning that the adrenal gland usually will respond with increased function, unless there is adrenal insufficiency or endocrine deficiency. The endocrine system includes the pancreas (insulin mechanisms), thyroid, and hypothalamus. The hypothalamus is closely associated with the brain centers regulating mood and emotion.
• Depending on the condition of the patient concerning adrenal insufficiency, hypothyroid states, or adult onset diabetes or metabolic disorder, or concerning the patient with chronic depression, anxiety, or the patient taking various medications for depression or anxiety, the effects of estradiol benzoate will vary. Since chronic narcotic pain medication use may also affect prolactin levels dramatically, this may increase the adverse effects of the EB use.
• Estrogen benzoate coupled with excess production of prolactin in breast tissue cells (endogenous prolactin): this combination has been studied to explain the increase in breast cancer incidence with chronic EB use.
• Estrogen benzoate effects on the blood calcium levels: the endocrine system strives to tightly regulate blood calcium levels. Estrogen and parathyroid hormones are the main stimulators of this regulation along with hormonal Vitamin D3. Estrogen in the body consists of a family of chemicals, all interdependent and performing specific sets of tasks. Taking of synthetic estrogen benzoate will signal via a feedback system a decrease in production of estrogen family chemicals. Estrogen benzoate will not duplicate all of these chemical effects. The end result is a lack of sufficient regulation of many biological mechanisms in the body controlled by the estrogen family chemicals, including regulation of circulating calcium levels. It is very important to tightly regulate circulating calcium, since calcium is a very large molecule that is highly charged, and thus may easily lodge in the capillary beds of joints and in various tissues, especially when there is much muscular contraction or swelling that impinges the blood vessels. These calcium accumulations commonly lead to frozen shoulder, painfully inflamed tissues, muscle firing dysfunction, and decreased organ function.
• Estradiol benzoate effects on the diuretic hormones and kidney function in relation to chronic hypertension and swelling: since EB affects the hypothalamus, which signals the release of antidiuretic hormone, this may contribute to hypertension and swelling. Estradiol benzoate is used as an intramuscular injection in an oily base to provide slow release for contraceptive purposes.
• Estradiol benzoate effects on the thyroid function: thyroid function also is affected by the complex feedback mechanisms of the neuroendocrine system, with thyroid stimulating hormone regulating this function and this hormone regulated in the hypothalamus/pituitary gland complex that is directly affected by estradiol benzoate. Poor thyroid function may be the result of either direct thyroid dysfunction or problems with the hypothalamus/pituitary complex. Both the thyroid and its embedded parathyroid gland regulate circulating calcium levels, bone calcium deposition and absorption rate of calcium from the diet or supplement pills. In addition, the thyroid hormones regulate much of our metabolic rate, or overall energetic function in the body.
• Estrone: the least prevalent of estrogenic hormones in the body, secreted by the ovaries mainly, acts as a stored precursor that converts to estradiol as needed; synthesized from androstenedione, a derivative of progesterone. Estrone sulfate is a long-lived estrogenic hormone.
• Diethylstilbestrol (DES) and conjugated estrogens: conjugated estrogen typically is derived from a pregnant mare and the brand Premarin is given. It is predominantly composed of estrone. It has been used since 1942, and the FDA cites a Women's Health Study Initiative that shows that risks are similar to other synthetic estrogens, with increased risk of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosus in postmenopausal women using a combination of Premarin with medroxyprogesterone acetate during a 5 year period. DES was an early synthetic estrogen that was found to be a serious cause for birth defects when used to prevent miscarriage.
• Estropipate: a salt of estrone sulfate, and thus a conjugated estrogen with the risks mentioned above.

Danish researchers in 2006 found that of 1925 men studied in military physicals, men conceived of women who had taken hormonal fertility treatments had 46% less sperm concentration in the testes, and slightly smaller testes (.9mm).

Certain estrogens have caused serious birth defects in humans, especially DES, with developmental problems in the reproductive & urinary tracts and cancers of the cervix and vagina developing at child bearing age.

CAUTIONS: risks must be weighed against the benefits

• Growth of bones in children may be affected, as well as vaginal changes and vaginal bleeding in young girls.
• Nursing mothers may easily pass the estrogens through the breast milk, causing problems in the infant.
• Elderly people are especially sensitive to estrogen therapies and may easily develop side effects, especially stroke and heart problems, breast cancers and memory disorders.
• Many medications may have negative interactions: acetaminophen (Tylenol), antibiotics, Tegretol, Antabuse, Depakote, Aldomet/methyldopa, Mellaril/phenothiazines/Compazine/Thorazine, anti-seizure medications/Dilantin, valproic acid.
• Many medical problems may indicate a reason for caution or avoidance of hormone therapy: asthma, calcium imbalance, diabetes, high cholesterol or triglycerides, inflammatory disorders, thyroid deficiency, blood clotting, seizure disorders, heart problems, kidney problems, liver problems, migraines, autoimmune disorders, cancers, endometrioisis.

SIDE EFFECTS (listed on drugs.com):

• Prolonged use increases risk of uterine cancers and breast cancers. Evidence published in the New England Journal of Medicine in 2009 confirms that cancer risk falls sharply when women stop synthetic hormone replacement. To see the latest findings, click here: http://news.bbc.co.uk/2/hi/health/7869679.stm
• Increased blood clotting with HA, breast pain, vaginal bleeding, irregular menstrual bleeding, stomach pain.
• Abdominal bloat, cramps, acid stomach, anxiety, backache, loosening of the skin, chest discomfort, decreased urinary flow, constipation, confusion, depression, loose stools, dry mouth, eye pain, heartburn, metallic taste, irregular heart beat or palpitations, muscle spasms, pain and/or numbness and tingling in the hands, feet, face, knees, groin, legs, calves, face, back or neck, pelvic pain, bladder pain, loss of appetite, nervousness, increase digestive gas, indigestion, stuffy nose, sudden sweating, insomnia, tiredness.

Depression in the use of hormonal replacement and oral contraceptives: This has been a major health problem linked to synthetic hormone use. Recent studies show that this is linked to induced metabolic deficiencies, especially Vitamin B6 pyroxidine, which leads to an increased excretion and deficiency of tryptophan (serotonin precursor) and methionine. Supplementation to correct these deficiencies has showed remarkable improvement. This link between the estradiol system and the serotonin system is also linked to chronic fatique syndrome and fibromyalgia, with hormonal synthetics creating problems in these complex systems.

Information Resources

A number of FDA warnings were issued to the public in recent years concerning synthetic hormone drugs. These warnings reflect a conservative view on the risks and are naturally tempered by objections from the pharmaceutical manufacturers, who exert much influence on our government:

1. A 2008 followup of the women in the 2002 Women's Health Initiative trial of synthetic progestiin estrogen hormone therapy, that was halted due to risk of breast cancer etc. for the women, shows that increased risk for breast cancer continues after halting the drugs, while benefits cease. This is from the National Cancer Institute: http://www.cancer.gov/ncicancerbulletin/NCI_Cancer_Bulletin_030408/page3
2. The 2004 FDA warning concerning progestins and estrogen: http://www.fda.gov/cder/drug/infopage/estrogens_progestins/Q&A.htm
3. The 2007 FDA warning concerning progestins and estrogen: http://www.fda.gov/cder/drug/infopage/estrogens_progestins/default.htm
4. A July 29, 2010 FDA warning on the potential for spray mist topical synthetic estradiol to cause adverse hormonal affects in children that come into physical contact with the patient, producing early puberty and abnormal breast growth, as well as other signs of hormonal imbalance, in both female and male children: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm220185.htm
5. A report in 2010 in TIME magazine reveals that the incidence of girls reaching puberty between the age of 7 to 12 has doubled in recent years, compared to 1997. This high incidence is primarily in the Caucasian population, according to the Breast Cancer and the Environment Research Center, and reflects increased exposure to hormonal drugs and environmental chemicals, as well as the hormonal effects of metabolic sundrome in children: http:/www.time.com/time/health/article/0,8599,2009341,00.html
6. Studies as far back as 1994 confirmed that progestins did not protect well against prescribed estrogen stimulation of endometrial tissue growth that is considered the mechanism of eventual cancer cause: http://www.ncbi.nlm.nih.gov/pubmed/7951564?dopt=Abstract
7. A 2006 study at the Center for Clinical and Basic Research, Ballerup, Denmark, found that synthetic estradiol plus progestins present significant risks for patients with metabolic syndrome and insulin resistance: http://www.ncbi.nlm.nih.gov/pubmed/16766431
8. Study findings regarding the rate of osteoporotic bone loss from DepoProvera, a progestin-only hormonal contraceptive injected every three months: http://www.nichd.nih.gov/news/releases/bone_loss.cfm
9. FDA update warnings were issued in 2005 concerning the popular Ortho Evra contraceptive patch: http://www.fda.gov/bbs/topics/news/2005/NEW01262.html
10. In 2009, the head researcher for the phase 2 and 3 clinical trials of the vaccine for human papilloma virus (HPV) spoke out with concerns about the efficacy of the vaccine strategy, effectiveness beyond 5 years, and the risk-versus-benefit of this strategy in the United States: http://www.cbsnews.com/stories/2009/08/19/cbsnews_investigates/main5253431.shtml
11. An amazing amount of fraud in published studies of hormone replacement therapy in 2002 was uncovered by Charles Grassley and a senate committee, which uncovered direct manipulation of PremPro studies by Wyeth when HRT sales plummetted: http://www.startribune.com/business/37023559.html
12. A study of estriol in the non-pregnant woman was conducted at the Boston University School of Medicine in 2010, showing that the estrogenic effects were probably mild in the non-pregnant pre-menopausal female, but could prove to make a significant contribution to the post-menopausal woman: http://jcem.endojournals.org/cgi/content/abstract/42/1/1
13. A study of estriol in the non-pregnant woman was conducted in 1981 and published in the Annals of Clinical Biochemistry, showing that estriol, contrary to popular belief, comprised 80% of the total estrogens in the non-pregnant female: http://www.ncbi.nlm.nih.gov/pubmed/7283367

The information on this website is not intended to be used as a specific medical advice or cure. Please consult with the practitioner or an appropriate physician, such as a licensed acupuncturist, naturopath, or medical doctor, to discuss the proper application of the information contained on this website.