Most people are familiar with the use of hormones for contraceptive purposes, and also the treatment of symptoms at menopause. These two aspects of use are most commonly known as birth control and hormone replacement therapy (HRT).

Off-label use of hormones, otherwise known as “non-contraceptive use of contraceptive hormones” or “hormone-based therapy” (HT), may be utilized in the treatment or preventive maintenance of illness. This essay explores the history and evolution of the business of hormones, and dynamics of hormone use.

Gaining popularity in the 1950s and 1960s, hormone replacement therapy was considered the best treatment for hot flashes and night sweats.  As of 2001 HRT for the symptoms of menopause was a 2.75 billion dollar industry (Seaman, 2003, p. 228).

Hormone use as a contraceptive is said to have begun in 1937 when experimentation showed that progesterone halted reproduction in rabbits.  According by Barbara Seaman, author ofpopular book, The Greatest Experiment Ever Performed on Women: Exploding the Estrogen Myth:

The experiment began in England in 1938, and it has continued for sixty-five years.  A British biochemist desperate to prevent Nazi Germany from cornering the world market on synthetic sex hormones published his formula for cheap and powerful oral estrogen. Within months, thousands of doctors and scores of drug companies around the world were working with this formula” (Seaman/NYWICI, 2003, p. 1). 

Ortho-McNeil Pharmaceutical offers a less dramatic historic introduction for progesterone in their time line of the history of birth control.  In the early 1940s an American chemist named Russel Marker produced progesterone from the roots of wild Mexican yam, and in 1949 University of Pennsylvania scientists produce synthetic progestins.  Soon, two synthetic oral estrogens (mestranol and ethinyl) [were] successfully developed (Ortho-McNeil Pharmaceutical. 2002-2005, pp.1-3).  In 1960 the first oral contraceptive, Enovid, was placed on the market and “family planning was revolutionized” (MedPage, 2005, p.1).  Estrogen and estrogen/progestin combinations were viewed as an absolute commercial success, and mass marketed for birth control, menopause, and even as a youth preserving beauty treatment; it was also prescribed for the prevention of heart disease and dementia.  Some of these claims were true, some were false. The doses were all very high.
In 2002 a National Institutes of Health (NIH) study confirmed some problematic aspects of extended hormone based therapy.  As of 2005 the media and the medical industry know that hormones can be safe and beneficial, but there is also proof that utilized in an incorrect manner, taken in too high of a dosage, or for too long, hormone based therapies can be very hazardous to your health. As a health consumer/patient it is important to understand the facts and debates surrounding hormone based therapy treatments.

The Women’s Health Initiative (WHI) study

In 1991 NIH began the Women’s Health Initiative (WHI)10, a “set of studies involving healthy post-menopausal women that were carried out in 40 U.S. [centers]” (Health-Canada, 2005, p. 1).  There were two branches of study:

1.  16,000 (+) post menopausal women aged 50-79 who had not had a hysterectomy were given either combined estrogen/progestin pills or a placebo.

2.  10,000(+) women who had a hysterectomy were given estrogen pills or a placebo.
In July, 2002, WHI halted study 01, in which women were given combined estrogen/progestin treatment due to findings that these women were showing a higher percentage of disease than the women being given a placebo.  There were:

A.  Seven more cases of coronary disease (37 on combined HT versus 30 on placebo).
B.  Eight more cases of stroke. (29 vs. 21).
C.  Eighteen more cases (and two fold greater) of blood clots in the lungs and legs.
D.  Eight more cases of invasive breast cancer.
E.  Six fewer cases of colorectal cancer.
F.  Five fewer cases of hip fractures.

In March, 2004, study 02 was complete.  The findings revealed that estrogen therapy:

A.  Did not increase or decrease the risk of coronary heart disease.
B.  Did not increase the risk of breast cancer.
C.  Increased the risk of stroke.
D.  Decreased the risk of hip fracture (in women who have had hysterectomy).
E.  Increased the risk of dementia.
F.  Increased the risk of diminished mental capacity.

                                                                         (Health-Canada. 2005; Speroff, L. 2005.)

In August of 2005 The World Health Organization (WHO) published its report on contraceptives and HT, and “toughened its classification” (ABC On-line, 2005, p.1) after findings revealed that long term use and high dosages do have carcinogenic effects.  Professor Boyages, Director of the New South Wales Breast Cancer Institute was quoted as saying that the research, “indicates that HRT might increase the chances of developing breast cancer by less than 1 percent over a five year period”, and continued with, “... it is important for women to understand both the risks and the benefits associated with HRT” (ABC On-Line, 2005, p. 1).

Unfortunately, the way in which the media conveyed much of the information surrounding the studies to the public, a frenzy of fear started which led to many women not knowing what the mode of treatment was for their situation.  Would they die of strokes?  Blood clots? Gynecologic or breast cancers? Would they suffer from bone density loss? Would they go insane?   The issue of hormone based therapies became convoluted in confusion. Law suits against large pharmaceutical companies have become common.  Many women began exploring complimentary and integrated medicine as an alternative to long term hormone use.  Others are still taking hormones, but are unsure what the long term effects may be on their overall health. 

There is also a portion of women on hormone based therapies who have not been represented in the aforementioned studies.  Government research has involved menopausal and post-menopausal women over 50, or women using contraceptives.  Comparatively little attention has been focused on the non contraceptive uses of contraceptives, medical defined as the “pharmacotherapeutics of gynecologic hormone therapy” (Rousseau, 1999, p. 545), where young women are placed on hormones for the treatment and/or maintenance of diseases and conditions of the reproductive system.  Statistics are hard to find, though “[t]he use of hormones by women throughout the life cycle is becoming more common for the treatment of infertility, certain cancers, and various gynecologic problems such as endometriosis and fibroids (Rousseau, 1999, p. 545), and also PCOS  since the U.S. Federal Food and Drug Administration approved off-label uses of contraceptive hormones.

If a form of hormone therapy is being suggested as preventive measure against the negative effects of a condition, or as maintenance, it is important to understand what most of the media based / health consumer information available is referring to with respect to the dangers of use; from there, you will then have to research how that information may be different to accommodate your specific situation.  What is good for a 19 year old woman with endometriosis who does not want to bear children, may not be as good for a 25 year old with ovarian cysts who wants to have a  husband and a handful of babies.  As we age, those differences only increase. 

Hormone-Based Therapies

Most often the health consumer will hear about hormone based therapies with respect to menopause, so let’s begin there.  In October of 2004 the North American Menopause Society (NAMS) released a position statement on Recommendations for estrogen and progestogen use in peri- and postmenopausal women in Menopause: the journal of the North American menopause society.  The researchers, called the “2004 HT Advisory Panel”, consisted of thirteen high level medical and research professionals who spent two years studying the “clinical uses of estrogens and progestogen in women through and beyond the menopause transition” (Menopause, v. 11, (6), 2004, p. 589) in an effort to confirm the risks and benefits, along with the areas necessitating more research, on hormone based therapies.  It was as a result of the “plethora of new clinical trial data” (Menopause, v.11, (6), 2004, p. 580) between 2001 and 2003 that the Society decided to organize a specific panel to address the needs of the medical industry, and the public the industry serves. The Panel confirmed that there was a significant need for “uniform and consistent terminology” for all hormone related therapies, and established the following eight categories:

1. ET                     estrogen therapy.
2. EPT                   combined estrogen-progestogen therapy.
3. HT                     hormone therapy (encompassing both ET and EPT).
4. CC-EPT            continuous-combined estrogen-progestogen therapy
                             (daily administration).
5. CS-EPT             continuous-sequential estrogen-progestogen therapy
                              (estrogen daily / progestogen added in set sequence).
6. systemic ET/EPT   preparations of ET or EPT that have a systemic, not solely vaginal, effect.
7. local ET                 preparations of ET that have a predominantly vaginal, not systemic effect.
8. progestogen           encompassing both progesterone and progestin.

In most health consumer articles the reader will find that hormone replacement therapy (HRT) and hormone therapy (HT) are the predominant references.  In the consumer sense, these terms are often interchanged as generalized hormone therapy modalities.  A physician, however, would (or at least should) utilize the formal medical standard that is now being requested by research and government agencies.

To enhance an understanding of the eight categories of hormone therapies for the purpose of advocacy, it is important to understand what kinds of estrogen and progestogen are available.

Hormones:   Estrogen, Progesterone, Testosterone

1. Estrogen:  The name of a group of hormones which include estrone, estradiol, and estriol.  Estradiol is produced by the ovaries each month from menses to menopause.   Estrone is formed by estradiol. After menopause, estrone is the primary estrogen, as opposed to estradiol before menopause.  It is produced by the adrenal glands and the ovaries, and is derived from body fat.   Estriol is produced during pregnancy in the ovaries and placenta.
2. Progesterone: A precursor to other hormones; creates and helps to balance estrogen, testosterone, and cortisol.
3. Testosterone:  Produced in the ovaries and adrenal glands; influential in forming tissues, contributing to strength, energy, and sexual arousal.

The Purpose of Estrogen and Progestins

It is understood by most women that estrogen is a guiding force in their menstrual cycle, and that estrogen depletes during menopause, creating symptoms such as hot flashes, night sweats, mood swings, vaginal atrophy, and other points of discomfort.  Progestins are necessary to balance the hormonal cycle, and without them, estrogen can over stimulate the lining of the uterus, creating hyperplasia. Estrogen is most often given to women to assist with symptoms of menopause, where as progestins are “recommended for women with a uterus who are on estrogen therapy to counteract the effects of estrogen on the uterine lining (Seaman, 2003, p. 231).

Progestins with Respect to HRT for Menopause

There are natural progestins (progesterone) and there are synthetic progestins.  According to Barbara Seaman, “[both] are made in the lab, and even synthetics can be concocted from natural products.  There difference between the two is not their source - whether they come from soy or yam or are developed in a test tube.  The distinction lies in their basic molecular arrangement.  If the chemical structure of the product identically matches that of a woman’s naturally occurring hormone, it is considered to be natural” (Seaman, 2003, p. 231).

Estrogen with Respect to HRT for Menopause

It is important to remember that estrogen is not one substance, but rather three separate hormonal substances.  Estrogen is a “blanket” term for all the categories of estrogen: estrone, estradiol, and estriol.  One of the factors involved in the controversy over use of estrogen replacement therapy (ERT) is that if only one form of estrogen is used, the body is removed from its natural state of balance.  When only one kind of estrogen is utilized, without any progestins, it is called “unopposed estrogen”, which can lead to uterine cancer.  Only in women who have had a hysterectomy is unopposed estrogen recommended.  There are many forms of estrogen:

1. Conjugated Estrogens: Two or more compounds synthesized to create a chemical compound or product.  (e.g.: the urine from numerous horses is synthesized with estrone to create a name brand estrogen product which would then be defined as a conjugated estrogen.)
2. Estradiol Based Estrogens: Used to mimic the estrogen lost at the onset of menopause. Converts into estrone.
3. Estropipate-Based Estrogens: Plant derived from crystalline estrone; a by-product of estriol and conjugated estrogens due to the manner in which the body processes it.  Estropipate is the weakest form of estrogen available.
4. Estrified Estrogens: An alternative to conjugated estrogen; plant based from yams soy. 
5. Combined Therapy: Originally, most women were prescribed ERT, utilizing only one form of estrogen in hormone based treatments.  This generated an increase in endometrial cancer.  Doctors than began prescribing a combination of ERT with progestins sequentially added into the cycle. There are studies that now show that combined therapy may cause breast cancer, so it is recommended that a risk-benefit ratio analysis be done when combined therapy is being considered, and also that use of the estrogen/progestin combination is short term.

Hormones as Oral Contraception

Oral contraceptives have been available for almost fifty years in the United States.  Statistics show that as of 2005 approximately 11.6 million American women use a form of contraceptive pill.  Despite all of the debates, oral contraceptives have come to be regarded as generally safe for most women, especially with respect to past forms of preventive means against pregnancy.  Ortho Tri-Cyclen Lo’s promotional site includes a “Pre-20th century” view into birth control which includes Chinese women once drinking mercury to prevent pregnancy, the Ancient Greeks consuming dilated copper, Italians drinking tea with mule’s hoof, Africans drinking gunpowder and camel foam, and Canadian Indians ingesting alcohol brewed with dried beaver testicles. (Ortho-McNeil, 2004, p. 1). Is it any wonder that women have little reservation about taking a simple, little pill?

During the 1950s pharmaceutical companies conducted large scale testing of the contraceptive pill.  These tests were so successful that in the 1960s the Food and Drug Administration (FDA) approved the first oral contraceptives to be sold in the United States.  Ortho Pharmaceutical introduced its oral contraceptive in 1963.  It was very popular.  It was also very strong in comparison to today’s contraceptives, and the progesterone component has since been improved15 (MedPage Today, 2005, p. 2). In the early 1970s Ortho Pharmaceutical introduced new oral contraceptives with a decreased dosage of estrogen and progestin. Oral contraceptives with both estrogen and progestin are called “combination” pills. In 1973, a progestin only pill was released to the public.  It is called a “mini-pill”.  By the early 1980s bi-phasic and tri-phasic pills were introduced to the public.  Containing both estrogen and progestin, the progestin levels are sequentially varied during the monthly cycle.  Now, there are many popular variations of, and alternatives to, oral contraceptives.

1. Plan B and Preven are “morning after” pills, which work when taken up to 72 hours after sexual intercourse.
2. Ortho Evra is a contraceptive patch.
3. Depo-Provera and Lunelle are contraceptive intramuscular injections administered every three months.
4. In Europe and parts of Asia contraceptive implants are available.
5. Overseas intrauterine devices are available.
6. Globally, condoms, female condoms, and diaphragms are available.
7. Tubal ligation and vasectomy are surgical options.

Non-Contraceptive Uses of Contraceptives

In 1988 the FDA “[recognized] several potential non-contraceptive health benefits of pill use” including a decreased incidence of ovarian cancer, endometrial cancer, pelvic inflammatory disease, ovarian cysts, benign breast disease, iron deficiency anemia, and dysmenorrhea  (Ortho-McNeil Pharmaceutical, 2002-2005, p. 3).  Current uses include estrogen, progesterone, and combined therapies for the treatment of PCOS and endometriosis. These off-label uses of contraceptives are commonly defined as hormone based therapies or hormone based therapeutic maintenance for pre-existing conditions or disease, and became available as a companion treatment to surgery officially beginning in 1995, though articles began to appear in medical journals between 1993 and 1995. 

As of 2005 oral contraceptives, long term intra-muscular injection contraceptives, and even the “morning after” pill, RU486 have established off-label uses for the treatment of endometriosis and PCOS.  Due to political differences on the morality of these methods for preventive care/maintenance, not all possible hormone based therapies are available to all women.

            End of segment. Complete references and footnotes available by request

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