While some hormone modulation protocols are gender independent, several are obviously female specific. The following presentation addresses these female-specific hormone issues: menopause and female sexual dysfunction.

Menopause

The average American woman’s life expectancy currently exceeds 81 years, so most women can expect to live more than one third of their lives well beyond childbearing years. Today menopause is no longer the hush-hush topic of their grandmothers’ generation. Both the non-medical and medical communities throughout the country now openly address the implications of menopause. Billions of dollars are spent each year on advertising, targeted at the 44 million-plus baby boomer women who are near or in the menopausal category. 

Menopause refers to that time in every woman’s life when menstruation ceases completely. As ovaries decrease their output of estrogen and progesterone, women begin experiencing the effects of suboptimal levels of these hormones. In addition to signifying the end of a woman’s ability to have children, declines in these female hormones affect the entire endocrine system. This process takes approximately three to five years to complete. The early phase or transitional phase is referred to as the climacteric, or perimenopause. Menopause is considered complete when a woman hasn’t had a period for a full year. Although timing varies from woman to woman, menopause is generally completed by the time a woman reaches her early to mid-50s. 

Testosterone (also produced in the ovaries) and growth hormone (produced by the anterior pituitary) also are reduced during menopause. As the levels of all of these key hormones diminish, profound changes begin occurring with growth and metabolism, affecting breasts, vagina, bones, blood vessels, gastrointestinal tract, urinary tract, cardiovascular system, skin, brain and energy levels.

What To Expect At Menopause & Beyond 

Every woman is an individual, but generally speaking, there are a number of adverse consequences that can be anticipated. Though some side effects may be considered temporary nuisances to be “toughed out,” the reality is the decline of a woman’s hormonal levels results in changes that can seriously affect her physical and mental health as well as her prospects for longevity. 

Vasomotor Symptoms

The most common symptom associated with menopause is hot flashes—a sudden sensation of intense heat. Some women actually experience dermatologic changes, such as breaking out in red blotches on the chest, back and arms. Some sweat profusely; many also experience cold and shivering until their bodies readjust. This frequently occurs during the night, resulting in insomnia, which is a common complaint among menopausal women. While many women never experience hot flashes, others can endure them for up to 30 minutes at a time. For most women, symptoms last two to five years. In fact, 1 out of 20 women have persistent symptoms. As reported in Lancet – 20% of women can have symptoms for up to 15 years! 

While the exact pathophysiology is not fully understood, they are thought to be the result of changes in the hypothalamic thermoregulatory set point occurring with the endocrine changes of ovarian failure. Both estrogen and serotonin are known to have input to this center. 

Women with high anxiety were nearly five times more likely to report hot flashes. According to Woods et al, many factors account for the variability in vasomotor symptom reports, including stage of and progression through the menopause transition; endocrine levels and change patterns in ovarian, pituitary and hypothalamic function; body mass index; health behaviors (smoking, nutrient intake, exercise/activity patterns, use of alcoholic beverages and caffeine;) race and ethnicity; socioeconomic status (indicated by education, income, occupation and perceived income adequacy and personal characteristics, such as affect, self-consciousness and attitudes toward menopause and aging). 

According to Freeman et al, in the Penn Ovarian Aging Study (POA), anxiety was associated with menopausal hot flashes, after adjusting for other variables, including menopause stage, smoking and estradiol levels. Anxiety preceded hot flashes in the cohort studied. Freeman looked at a population-based cohort of midlife women and followed them for six years. At the six-year endpoint, 32% of the women were in the early transition stage, while 20% reached the late menopausal transition or were postmenopausal. Reports of hot flashes increased with the transition stages, which were determined by bleeding patterns. At endpoint, 37% of the premenopausal women reported hot flashes—48% of those in the early transition, 63% of women in the late transition and 79% of the postmenopausal women. Anxiety scores were significantly associated with hot flashes and were also significantly associated with the severity and frequency of hot flashes (each outcome at P < 0.001). Compared with women in the normal anxiety range, women with moderate anxiety were nearly three times more likely to report hot flashes. (1) 

These findings contribute to a better understanding of who is most likely to experience symptoms, how frequently and with what consequences it holds for their lives. Taken together with earlier reports of personal characteristics influencing symptom experiences, these relationships enlarge our understanding of who is most likely to experience vasomotor symptoms.  

Vaginal & Urinary Tract Changes
As hormone levels decrease, the walls of the vagina become thinner, dryer, less elastic and more susceptible to infection. This condition can also make intercourse uncomfortable.

In addition, there is an alteration in the normal vaginal flora.  Tissues in the urinary tract also change with the decrease of hormonal levels and can cause incontinence and an increased susceptibility to urinary tract infections. Fortunately, these changes are readily reversible and atrophy usually begins to improve within as little as 2 weeks of instituting therapy with good control achieved by the 1 to 3 month mark.   

Loss of Libido
Rarely discussed, the loss of sex drive is another by-product of the menopausal experience. Women generally have 1/10^th to 1/20^th of the testosterone levels that men have. The waning of pre-menopausal levels of testosterone can be a contributing factor to a woman’s loss of desire for sexual intercourse. 

Emotional Changes
For some women, menopause heralds a period of enormous freedom. For others, it is a roller coaster ride with emotional peaks and valleys. In many, depression becomes an all-too-frequent companion. Frequently, the mood disturbance also includes anxiety, strongly associated with menopause. There is no consensus as to just how much lifestyle, alteration of family roles, changing social networks and empty nest issues contribute to the emotional changes of post-menopausal women. However, it’s clear hormonal decline is a major contributor to this emotional instability. 

Osteoporosis
Bone mineral density and risk for osteoporosis are a major public health concern. Ten million people already have the condition; 34 million more have osteopenia, the precursor to osteoporosis.  One out of every two women will have an osteoporosis-related fracture in her lifetime. (2) Of the more than 2 million American men with osteoporosis, one out of every four over 50 will have an osteoporosis-related fracture in his lifetime. (1) Of the 80,000 men who sustain a hip fracture annually, one-third will die within a year.  

Osteoporosis is responsible for more than 1.5 million yearly fractures, including 700,000 vertebral fractures, 300,000 hip fractures, 250,000 wrist fractures and more than 300,000 fractures at other sites. National direct expenditures (including hospitalization and nursing home care) cost the economy $14 billion each year..(2)Slide01 

Osteoporosis is primarily a manifestation of estrogen insufficiency; however, testosterone, progesterone and growth hormone also play a role in bone density maintenance. The greatest degree of postmenopausal bone loss is associated with thin habitus, Caucasian ethnicity and positive smoking history.  Since adipose tissue is a source of estrogen production, the presence of adipose tissue can mitigate bone loss.  

Weight-bearing exercise promotes bone mineral density retention since any given bone density is associated with stronger bone.  Diet and general health have been variably associated with maintenance of bone mineral density.  Inflammatory mediators suppress bone formation by decreasing osteoblast function—the same way bone marrow/RBC production is affected by the same mediators. Control of inflammatory disorders reduces cytokine formation with an associated decrease in bone loss.  

Cardiovascular Disease
Heart disease is the number one killer of American women. It is responsible for over half the deaths of women over age 50. After menopause the incidence of cardiovascular disease increases. Smoking and a family history of heart disease give women a higher chance of developing cardiovascular disease (as well as other serious diseases). When coupled with low estrogen levels, the risk is much higher than either one alone. As a direct result of estrogen deficiency, LDL cholesterol increases and HDL decreases. As LDL levels rise, fat tends to accumulate in artery walls, creating plaques. The falling levels of protective HDL (high-density lipoproteins) make it impossible to remove the fat deposits, eventually resulting in the occlusion of the vessel lumen. Early recognition, lifestyle changes and hormone modulation (bioidentical and taken by the proper delivery route) have been show to be quite effective in reducing the incidence and severity of cardiovascular disease in post-menopausal women.

Risk Factors for Symptoms
There are modifiable risk factors for increased symptoms of menopause, which include diet, being underweight, cigarette smoking, exercise patterns, depression and anxiety. The non-modifiable risk factors are race, family history and menopause at younger age. 

The relief of acute symptoms is the primary motivating factor for most women seeking hormone replacement therapy. While the acute symptoms of menopause typically diminish even in unsupplemented women—on average, about four years after the beginning of menopause—the rationale for continued therapy is based on the underlying physiologic benefits of hormonal therapies. The optimum duration of therapy has not been definitively demonstrated.

Estrogen Therapy
The greater part of any discussion regarding menopause should be dedicated to the role of estrogen in the maintenance of female health. Estrogen plays a greater and more wide-range role in hormonal physiology than progesterone—with the bulk of literature regarding progesterone’s role in menopausal therapy as a balance for any potential pro-proliferative effects of estrogen on uterine tissue. There will be some data presented regarding other potential benefits of natural progesterone replacement, but we will start with estrogen.

Classic texts cite estrogen production as being 60% from ovarian tissue and 40% from adipose tissue. These proportions are probably not accurate since estrogen levels can fall from peaks of greater than 700 pg/ml or an average of 100 pg/ml before menopause to near zero afterward. At age 60, an average unsupplemented female will have lower estrogen levels than a similarly aged man.

Physiologic effects of estrogens include maintenance of uterine and breast tissue, significant effects on vaginal mucosal thickness and lubrication; aiding in maintaining proper vaginal flora. Additionally, estrogen is associated with quality retention of the distal urinary tract. Local vaginal and systemic effects play an important role in libido and aiding sexual function.

The presence of estrogen is also associated with more advantageous cardiac valve and blood vessel elasticity with notable declines seen after menopause. Maintenance of estrogen is also associated with better lymphocyte function, maintaining lipid profiles and the continued expression of steroid receptors.

Newer studies have demonstrated estrogen’s beneficial effects on cortical function, as demonstrated on PET scans. A negative correlation exists between estrogen levels and risk for Alzheimer’s disease. In addition, maintained estrogen levels have a strong correlation with significant reductions in risk for colon cancer and macular degeneration.

The presence of estrogen is associated with improved glucose metabolism in all spheres: better insulin sensitivity, decreased lability of glucose levels, improved insulin kinetics and lower HBA1C levels. These benefits also are demonstrated by the association of estrogen levels and decreased central adiposity.  Other studies have shown the correlation between estrogen levels and sleep quality, and skin elasticity retention and thickness of the dermal basal layer.

Estrogen replacement has been shown to improve mood scores in depressed subjects. The influence of estrogen and retention of bone mineral density is well described.

While the benefits of estrogen maintenance have been mentioned previously, there are several health considerations regarding estrogen hormone replacement therapy (HRT), which must be taken into account when deciding whether or not to undertake therapy or how long to continue it.

The following discussion will focus on risk/benefit aspects of estrogen HRT with regard to prevention of coronary artery disease, osteoporosis, cognitive decline and associated risk for uterine cancer, breast cancer and venous thrombosis. Also the choice between synthetic and bioidentical hormones will be discussed. Additionally, the route of hormonal delivery is of critical importance with some forms demonstrating clear-cut adverse effects.

Any discussion of the risks versus benefits of HRT must first be put in perspective. The vast majority of the studies to date (including those cited in this material) were performed on oral conjugated equine estrogens and synthetic progestins. CEE contains forms of biologically active estrogens, which are not natural to humans. In addition, the oral forms (discussed later) have been shown to increase CRP, a biomarker of inflammation. Studies continue to mount, linking inflammation to increased heart disease and stroke risk, cancer and even Alzheimer’s disease. The oral delivery route can also decrease IGF-1 levels as well.

Estrogen & Cardiovascular Function
Coronary artery disease accounts for one third of all female deaths. In women, CAD typically appears at a later age than for men, but women have a higher incidence of mortality after a first M.I. than men and are less likely to be diagnosed or treated as early as men. The clinical data regarding the prevention of CAD in women with hormone replacement therapy is strongly directed at primary prevention, with poor results found when considering hormone replacement as secondary prevention. 

Maintenance of estrogen levels after menopause is associated with more readily retained HDL levels and more advantageous LDL and Lp (a) levels. It is also correlated with lower levels of lipid oxidation markers. Tissue studies have demonstrated greater endothelial integrity and lower likelihood of plaque rupture in women with retained estrogen levels. 

Flow studies have demonstrated that maintenance of hormone levels are associated with greater retention of coronary artery diameter and retained valve pliability.Slide02

Regarding the impact of ERT/HRT on coronary artery disease (CAD) prevention, the Wenger meta analysis of the 30 largest hormone replacement studies showed a range of 35% to 50% reduction in risk. ERT was judged equivalent to HRT, with the PEPI study slightly favoring HRT. Considering one in three women will die from CAD, this is a profound reduction in mortality risk. (3) 

Budoff et al conducted an observational study, looking at the benefits of estrogen on cardiac function. The results are in accordance with the WHI study, demonstrating no benefit of estrogen plus progestin compared with no therapy. However, women taking unopposed estrogen demonstrated a significant slowing of subclinical atherosclerosis, compared with non-HRT and estrogen plus progestin. (4) 

The American Heart and Estrogen/Progestin Replacement Study (HERS), a large (n=2763) multicenter randomized study, was designed as a secondary prevention trial to evaluate cardiac outcomes of HRT (CEE+MPA) vs. placebo on a population of women with a previous history of coronary heart disease. It showed no decrease in risk of MI or CAD in HRT users. It demonstrated a 50% increase in cardiac events in the first year of treatment in the HRT arm. In the second and third year, it remained elevated. During years four to eight, there was a tie between cohorts and controls. Only after the eight year was an advantage seen in the HRT group. No difference existed in coronary artery diameter between ET, HRT and control groups. Overall an increased risk of MI, CAD death, stroke or venous thromboembolism was seen in the ET and HRT groups. Again, it must be stressed that these were women with known preexisting heart disease at the start of the trial. Breast cancer risk was not increased in ET and HRT groups; no benefit of HRT on cognitive function was noted. (5,6) Slide03  Slide04

Judith Hsia and colleagues analyzed data from the estrogen-only portion of the WHI study. During the course of the trial, the women taking hormones experienced 201 coronary events, which included heart attacks and coronary deaths, while those taking placebo had 217 events. Overall, the risk was similar for women who took hormones compared with those who did not, though there was a suggestion of lower risk in women age 50 to 59.  

Among these women—a total of 1,396 between 50 and 59 at the start of the study—there was no significant reduction in myocardial infarction (heart attack) or coronary death among those taking estrogen. However, coronary revascularization was less frequent among women taking estrogen, as were several combined endpoints, such as myocardial infarction, coronary death and revascularization. “This trial may have been unable to demonstrate a significant difference in the risk of myocardial infarction or coronary death by age group because of the low event rate in young women,” the authors report. (7) 

Ouyang et al conducted an extensive review of the research and reports on HRT and the cardiovascular system in 2006.  They reported that randomized placebo controlled trials in older women have not shown any benefit in either primary prevention or secondary prevention of CV events with a concerning trend toward harm. (8) Slide06  

HRT & Deep Vein Thrombosis
Several studies have addressed the risk for developing deep venous thrombosis (DVT). The data preceding the HERS study demonstrated a range of two-four fold increase in risk associated with ERT/HRT. The HERS study delineated similar findings, describing a three-fold increase in risk. However, the HERS study was one of the first to attempt evaluating which subjects within a cohort were at risk; the study found the only positive predictor for increased risk was an age of greater than 52 when first initiating ERT/HRT. There were no other criteria associated with any increase risk for thrombosis. Also of note is that subjects who were using daily low dose aspirin or who had been taking statin drugs for lipid control actually showed a 50% decrease in DVT risk from baseline. (6)

A health maintenance program addressing the potential benefits of low-dose aspirin therapy obviates concerns regarding any increase in DVT incidence in patients on ERT/HRT.

Bone Mineral Density
The degree of improvement in bone mineral density (BMD) associated with ERT/HRT can be startling. In the PEPI trial, hip and vertebral bone density were tracked over a three-year period. Hip BMD declined by 2% over three years in subjects taking placebo, while improving 2% in subjects on HRT. The net outcome shows subjects on HRT had a 4% greater BMD than they would have without HRT. The findings for Vertebral BMD were even more pronounced, with a net difference of 7% to 8% after a three-year period on HRT. When considering BMD data, it is important to consider where a patient’s BMD “would have been” had they not been receiving HRT. (9) Slide08

Dr. Dennis T. Villareal (Washington University School of Medicine in St. Louis) and colleagues assessed the bone-related outcomes of 67 women with mild-to-moderate physical frailty and 75 years or older, who were randomized to receive HRT or placebo for 9 months. The HRT regimen consisted of conjugated estrogen at a dose of 0.625 mg/day and trimonthly medroxyprogesterone acetate at a dose of 5 mg/day for 13 days (long cycle HRT). The HRT treated group produced significantly greater increases in the BMD of the lumbar spine and total hip than did placebo, the researchers determined. HRT also resulted in significantly greater decreases in serum bone-specific alkaline phosphatase levels and urine N-telopeptide levels.  

“HRT has significant osteogenic effects in very old, physically frail women,” the investigators conclude. “However, fracture risk in very old women is due to multiple factors in addition to low BMD, including sensory and neuromuscular impairments, medications and environmental hazards. Further research is therefore necessary to elucidate the effectiveness of HRT…in reducing fracture rates and postponing disability.” (10) 

Hormone replacement therapy (HRT) significantly increases bone mineral density (BMD) in clinically important skeletal regions of frail elderly women, according to a report published in the Journal of the American Medical Association.  HRT has been established as an effective method of preventing osteoporosis, but the current findings indicate it has a protective effect in elderly women, who are already considered physically frail.   

Long-cycle HRT may be a valid alternative to conventional HRT with regard to protection against postmenopausal bone loss. (11) 

HRT & Cancer

Uterine Cancer
There is some agreement in the literature regarding the risk for diagnosis of uterine cancer and unopposed estrogen replacement. Studies have shown a consistent increase in risk, somewhere in the range of four- to nine-fold. This risk is associated with noncycling monotherapy at doses above what natural premenopause levels would have been. Even though risk for diagnosis was increased, when the data for mortality was reviewed, this risk was mitigated by the fact that mortality rates for this group was low due to the low invasiveness of tumors occurring within this context. (12) 

Of greatest note is the fact this increased risk does not appear in association with combined estrogen/progesterone therapy (HRT) with the use of progesterone, preventing the hyperproliferative effect of estrogens. This data is the cornerstone for the rationale for using combined hormone replacement rather than monotherapy. (12) 

A prospective three-year clinical study was conducted by Yang, et al, examining the effect of hormone replacement therapy on uterine fibroid growth among postmenopausal women. Thirty-seven postmenopausal women with uterine solitary fibroids were recruited randomly for HRT in a three-year program. All participants received 0.625 mg conjugated equine estrogen (CEE) and 5 mg medroxyprogesterone (MPA) daily.  The researchers found HRT does increase uterine fibroid volume statistically. However, its effect appears in the first two years of use. The increased fibroid volume begins to decline at the third year both in HRT users and non-users. Clinically, the increased effect of HRT on uterine fibroid of postmenopausal women should be not over-emphasized at least for three years of usage. (13) 

Breast Cancer

While the age-specific incidence of breast cancer increases with age to a lifetime risk of 1 in 8 (to 110 years of age), overall baseline breast cancer risk is 1:28 women, or 3.6%. The relative risk is a measure used to determine whether or not a characteristic is associated with a disease. It is the ratio of the incidence rate in an exposed group versus an unexposed group. Given the relative risk ratios from the literature at no increased risk to values of 1.14 to 1.3 (1.3 is using the most pessimistic data possible), it can be seen that actual risk increases from 3.6 baseline to 4.1% or 4.6% at maximum. A 30% increase in relative risk is an actual increase of 1%, regarding incidence. A 1.14 RR would equal a 0.5% actual increase. Correction for increased life span must be examined as well. Any population experiencing an intervention that increases life span would most likely experience an increase of cancer incidence since a portion of the population who would have died otherwise would instead be alive to develop cancer later. 

As a comparison, risk for death from cardiovascular disease (CAD) is reported to be as high as 50%. ERT/HRT reduces CAD risk by as much as 50%. Given that as many as 1,700 out of 10,000 subjects on ERT/HRT would live to age 80 who would have died from CAD shows the actual population benefit of ERT/HRT, even with the relative increase in breast cancer. 

To place relative risk for breast cancer in the proper context, it is worthwhile to translate relative risk to actual risk. This becomes even more important given today’s media habits of sensationalizing all types of data. As an example, according to relative risk, a change in risk for any event that increased from 1 per billion to two per billion would be a 100% rise in relative risk; a change from one per billion to one per hundred million would be a 1,000% rise in relative risk. When looked at based on actual incidence, it becomes easier to differentiate the actual impact of these statistical changes. Slide11

Many statistical analyses state increases in RR for diagnosis of breast cancer, but not in breast cancer mortality. Patients on ERT/HRT who do develop breast cancer are far more likely to have non-aggressive or lobular breast cancer with less aggressive cell types. Mortality from breast cancer should be examined in this context, which would further decrease RR regarding outcomes such as mortality. 

Studies by Sellars, (TA in the Annals of Internal medicine, 1997) and Willis (DB in Cancer Causes and Control, 1997) both point out reduced risk for mortality in women who have been on HRT relative to controls. The Willis study reviewed 422,373 subjects; Sellars reviewed 41,873 subjects. In the Sellars study, women receiving HRT had one half of the annual mortality rate of their untreated counterparts. (15,16) 

Cengiz et al found that although there was a statistically significant decrease in CA 15-3 levels in current E2 and E2 + NETA users and a decrease in CA 125 levels in combined regimens, this change is clinically not relevant in healthy postmenopausal women. (17) 

Daling JR, Postmenopausal women who take CHRT appear to be at an increased risk of lobular breast carcinoma. Data from this study suggest that neither ERT use nor CHRT substantially increase the risk of ductal breast carcinoma among women age < 65 years. (18) Pappo found that breast tumors in HRT users vs. nonusers were of a significantly lower stage and grade, accounting for a higher number of favorable histological types; but all other parameters were similar in the two groups. (19) 

In the Breast Cancer Detection Demonstration Project (BCDDP; 46,000 pts.), estrogen replacement (ERT) alone was associated with an increase in relative risk of 10% (relative risk, RR, of 1.1) and combined HRT showed a 30 % increase (RR of 1.3). 

The USC study (3,600 pts.) showed RR of ERT of 1.06 and HRT with an RR of 1.09. Cycling therapy revealed a 1.38 RR. In the 10 to 15 years of therapy group, there was no increase in risk. 

The National Health and Nutrition Examination Study (NHANES, 6,000 pts.) showed no increase in RR out to 22 years of therapy and a decline in RR to 0.5 baseline risk after 3 to 9 years. The Iowa Women’s health Study (IWHS, 37,000 pts.) showed similar findings.

The Creasman/Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) analysis (included 91% of all subjects ever studied) concluded that in total, studies ranged from no increase in relative risk to an upper limit of increased risk to an RR of 1.14. (3)Slide08

WHI Controversy

Ever since the results were first released to the press in 2002, the Woman's Health Initiative (WHI) has been highly controversial. To briefly recap: WHI was designed between 1991 and 1992 by the NIH and its National Heart, Lung and Blood Institute. The trial included 161,809 women, 50 to 79 years of age, who were assigned to either the observational study or one of the clinical trials of conjugated equine estrogen (CEE) plus or minus medroxyprogesterone acetate (MPA) vs. placebo. The study was finally begun in 1997, scheduled to run through 2005.  

However, the CEE/MPA arm was stopped prematurely in July 2002 when the number of excess breast cancers exceeded a predetermined threshold of the global risk index—a statistic that hadn't been validated previously and has yet to be validated. Interestingly, the CEE-only arm was allowed to continue until it, too, was terminated prematurely in March 2004, when the number of excess strokes exceeded that same questionable global risk index.  

Critics of the study point to flawed design, among other issues. The average age for menopause in this country is 51 years. The average age of enrollment in the study was 63.3 years, more than a decade later than the age at which most women begin HRT. When prevention is the intent of therapy, and chronic disease the end point, it is reasonable to assume that progression of any disease process is more advanced two to three decades later than when one would normally begin HRT intervention. The participants were not prescreened for heart disease. Without prescreening, some women certainly began the study with preexisting heart disease. It is a foregone conclusion that within that one to three years, a higher incidence of cardiac disease would have occurred—and in fact, it did. 

In addition, as will be discussed, oral forms of estrogen are proinflammatory; CEE contains over 30 biologically active forms of estrogen, not found in humans. The synthetic progestins used in most studies have been implicated in breast tissue proliferation and increased cancer risk, as well as increased cardiac events. 

At the time the CEE/MPA arm was stopped in July 2002, the press focused only on its putative negative effects, i.e., increased coronary risk and breast cancer, even though these results were not statistically significant. Never mentioned to the lay public was the decrease in the osteoporotic fracture rate and colon cancer incidence, which were statistically significant findings. In fact, WHI was the first study to demonstrate a decrease in fracture rate as a result of estrogen supplementation, not just an increase in bone mineral density.  

Recapping these findings, Cauley et al published WHI analysis in October 2003. He concluded estrogen plus progestin increases bone mineral density and reduces fracture risk in healthy postmenopausal women in all subgroups of women in WHI. This effect didn't differ in women stratified by age, body mass index, smoking status, history of falls, personal/family history of fracture, total calcium intake, past use of hormonal therapy, bone mineral density or summary fracture risk score. Note: The 24 % reduction in the hazard ratio was statistically significant. Clearly, the negative press allotted to WHI and its statistically insignificant findings—along with the dearth of publicity about its statistically significant beneficial findings—dramatically set back osteoporosis treatment. (20) 

Like the WHI study, the Nurses Health Study found no statistically significant increased breast cancer risk when estrogen therapy was used for less than 10 years, per Chen and Harvard researchers. They also said the longer a woman used estrogen, the greater her risk of breast cancer. For those who had taken estrogen for more than 20 years, the increased risk was highly significant. (21)

The NHS (a prospective cohort study) included postmenopausal women who had a hysterectomy and eventually included 28,835 women in the 2000-2002 follow-up period. A total of 934 invasive breast cancers were included in the analysis with breast cancer risk increasing with duration of unopposed estrogen among longer-term users—especially in tumors that were estrogen-receptor positive and progesterone-receptor positive, the researchers reported.  

Analysis of relative risks over 20 years found the risk began to increase after 10 years. By 20 years, it was more than 40% greater. The multivariate relative risks (RRs) and 95% confidence intervals (CIs) for breast cancer with current use of unopposed estrogen were as follows (P for trend .001): (22) 

The risk of estrogen-receptor positive, progesterone-receptor positive breast cancer was statistically significant after 15 years of current use (RR, 1.48; 95% CI, 1.05-2.07), the researchers said.  

The results were similar when the analysis was limited to women who were at least 50 years old and had had a hysterectomy regardless of menopausal status at the time; among postmenopausal women of all age groups; women older than 60; and women who started estrogen after age 50.

A clear effect of the conjugated equine estrogen dose could not be determined, the researchers said, because most of the women used the standard 0.625-mg dose. In an analysis of possible confounders, the researchers said although current estrogen users were younger, thinner and less likely to have a family history of breast cancer than never-users, these factors would have led to a decreased rather than a higher risk of breast cancer. Socioeconomic status was also not a factor. Given that all of the women were nurses, there would be less variation in socioeconomic factors to cause confounding.

Women who took estrogen for longer than 10 years may represent a different population, but the mammography patterns in shorter-term and longer-term users were similar; they were more likely to have had a bilateral oophorectomy than older women, neither of which would be associated with an increased breast cancer risk, Dr. Chen's group wrote.  

The women were also more likely to be thinner, per researchers, although further analysis found that among women who used estrogen for more than 20 years, the relative risks of BMI above and below 25 BMI were not significant.  

Per the researchers, there might be other confounders separating out the long-term users, although noting they controlled for most of the known breast cancer risk factors. Finally, Dr. Chen wrote that the increase in breast cancer risk with increasing duration of estrogen therapy suggests “a true biologic relationship.” (21) 

Women who take estrogen therapy for prevention or treatment of osteoporosis “typically require longer-term treatment and should thus explore other options, given the increased risk of breast cancer with longer-term use,” investigators advised.

Getting back to the WHI data, Creasman et al in an article, “WHI: Now that the dust has settled,” gives us some insight on what we should do with this data.  He says to publish data that may or may not be entirely true or certainly premature is a disservice to the medical profession and, most importantly, to our patients. The majority of the data published are not statistically significant even at the nominal level. For several decades, data from univariate analysis not remained significant in multivariate analysis have been disregarded in managing patients. Because much of the data presented in the WHI study falls into this category, why the big change to modify or change practice? Certainly, new significant data are important. Data in which the difference could be due to chance alone do not satisfy this time-tested edict. 

The final publications on this study that may satisfy our many concerns could pass medical scrutiny. Until then, this and other like publications should be taken with a grain of salt. (22) 

Putting Everything In Perspective

HRT & Dementia
Strong data exists relating low estrogen levels and risk for dementia, with equally strong correlations between having received hormone replacement therapy and reduced risk for (or delayed onset of) dementia. Tang found hormone replacement delayed onset of dementia and showed significant over-all reduction in total risk. In 2006, Schmidt reported hormone replacement therapy was associated with better cognitive performance on all evaluated test types vs. non-treated subjects.  The study also revealed decreased rate of ischemic brain damage associated with hormone replacement. (23) 

Manly reported an association between low estrogen levels and the development of Alzheimer’s disease.  Waring found that hormone replacement therapy was associated with a significantly reduced risk of Alzheimer’s disease. (24)

Along with duration of life, it is equally important to consider quality of life. Retained mental capacity rates as women’s greatest health worry as they age. Cognitive abilities correlate more strongly with a woman’s ability to continue independent living and her risk for institutionalization (vs. requiring minimal assistance) than any other measured parameter. This consideration outranks total lifespan and all other health issues in studies of women’s health and their concerns.

Route Of Estrogen Replacement & Its Effect On IGF-1 Levels

The delivery route of estrogens can have a significant impact on other variables and hormone levels as well.

Oral estrogens can have a significant negative impact on growth hormone levels. The Ho and Jannsen studies addressed the varying utility of oral vs. transdermal delivery of estradiol. The Ho study noted oral estradiol supplementation was associated with 20% lower IGF-1 levels vs. transdermal; oral delivery was associated with higher fat mass and lower lean body mass. (25) The Janssen study also noted a 20% differential in IGF-1 level between topical vs. oral hormone replacement therapy. (26)

The effects on LH levels and BMD did not vary with route of delivery.  

Transdermal and transmucosal delivery systems avoid the first-pass effects through the liver and may decrease the elevated bile acids and gall bladder disease and hypertriglyceridemia, occurring with oral estrogen preparations. 

Oral estrogens have been found to be proinflammatory in nature. Studies suggest transdermal routes may have a more favorable effect on the coagulation pathway and C-reactive protein. The increased risk of stroke associated with the oral forms of replacement is hypothesized to be mediated by inflammation and thrombosis. The transdermal forms do not appear to adversely affect coagulation activation and fibrinolysis.

Progesterone
The prevailing use of progesterone is in an adjunctive role with estrogen replacement. Progesterone mitigates any potential pro-proliferative effects that estrogen exerts on uterine tissue. In studies of combined estrogen and progesterone replacement therapy, the increase in risk that is seen on estrogen replacement therapy alone is negated.

There are reports of natural progesterone therapy being associated with improved self-report of mood and scores on mood evaluation testing. There may also be some improvement in sleep onset and duration. 

Some dosing caution is required. High-dose synthetic progestin therapy is associated with blunting of cardiac, lipid and cognitive benefits, seen with ERT or low-dose progesterone regimens. 

To date, there is conflicting epidemiologic evidence about the role of progestins in breast cancer. The majority of observational studies have examined estrogen-only regimens. The vast majority of studies have failed to obtain hormone levels before and during treatment making it impossible to know if sub-optimal, optimal, or supra-physiologic levels have been studied.  The statistical strength of recent epidemiologic studies showing increased risks with combined therapies is weak. 

Prior or current HRT use results in a paradoxically improved survival for patients with breast cancer.  Sustained progesterone may be inhibitory to malignancies already in place.  Because synthetic progestins are now widely used in postmenopausal hormone therapy; it is critically important their specific effects on breast tissue be clearly understood. 

Rigorous, large-scale, double-blind, randomized trials are clearly needed to clarify the role of progestins and breast cancer.  More long-term data are required on the clinical outcomes of non-oral routes of administration of bioidentical forms of estradiol and progesterone.  Clinical research, both observational studies and randomized controlled trials, are desperately needed to improve our ability to make the right choices for our patients.Slide13

Continuous-sequential estrogen-progesterone therapy (CS-EPT) Versus Continuous Combined (CC-EPT)

The benefit-risk profile of continuous-sequential estrogen-progesterone therapy (CS-EPT)-also  known as cyclical therapy—compared with continuous-combined estrogen-progesterone therapy (CC-EPT) and other HT needs to be elucidated. A review of the literature does not clearly demonstrate superiority of one method over another. 

Stevenson et al concluded transdermal continuous HRT had beneficial effects on vascular function and CAD risk markers, based on a randomized trial of the effects of transdermal continuous combination hormone replacement therapy on cardiovascular risk factors. Yet, other studies have suggested otherwise. In a 2001 review of HRT dosing regimens comparing continuous versus cyclical therapies, Shoupe concluded “although controversial, some studies suggest that continuous progestin therapy may prove most beneficial in regard to bleeding control, endometrial protection, and breast protection. On the other hand, protection from atherosclerosis may be better using cycling therapy.”

To further confuse the issue, Stahlberg et al concluded “The continuous combined regimens were associated with a statistically significant higher risk of breast cancer than the cycled combined regimens.”

Clearly, additional long-term data gathered by large-scale, double blind, randomized trials are needed to clarify the role of various hormone replacement regimens and ultimate health outcomes.

Summary

Looking at the evolution of ERT/HRT, there are now-low dose studies underway, trying to elucidate which levels of ERT/HRT will still provide benefit while minimizing any undesirable effect. As these dosing protocols are evaluated, it may trend dosing choices downward and allow further reduction in patient risk while maintaining the benefits. 

For women unable to undertake ERT/HRT, the use of Synthetic Estrogen Receptor Molecules (SERMs – Tamoxifen, Raloxifene) may contribute bone and cardiac benefits with no associated ERT/HRT risk. These molecules do not, however, ameliorate the symptoms of vasomotor instability or other subjective menopausal complaints. 

Indole-3-Carbinol is a naturally occurring compound, found in cruciferous vegetables. It has been found useful in primary and secondary prevention of breast cancer; in association with ERT/HRT, it may also be important for reducing any potential associated cancer risk.  

Testosterone
Symptoms of testosterone deficiency in women are decreased libido and sexual responsiveness,  depressed mood, diminished feeling of well-being, diminished cognitive function, increased risk for cognitive decline and Alzheimer’s, increased vasomotor symptoms, diminished bone mass, diminished lean mass, increased fat mass, hypercholesterolemia, poor glucose control.  Women’s testosterone levels can decline dramatically between ages 20 and 50.  Testosterone declines frequently precede menopause.  Total testosterone levels < 20 ng/dL are associated with declines in sexual arousal, genital sensation, libido and quality of orgasm.

Testosterone replacement in women is associated with many of the same benefits, seen in men.

Improvement is seen in these areas: cognition, libido, sexual responsiveness, mood, body composition, preservation of lean muscle mass, glucose metabolism and lipid profile.  

Reviews by Davis, SR; Burd ID, Sherwin, BB looked at the benefits of testosterone supplementation with regard to libido, sexual responsiveness and maintenance of healthy genital tissue. (27), (28), (29)  Reports by Sarrel, P and Gelfand, MM relate similar findings from clinical studies.  These same reviews point out the benefit of testosterone therapy for controlling vasomotor symptoms, mood, lean mass and bone density. (30,31)

Sarrel found testosterone did not constrict blood flow to either the fingertips or vagina. In fact, blood flow to the fingertips increased in those women taking testosterone compared to those in the estrogen-progesterone group.  Scientists examining monkey, dog and rabbit arteriesm also found testosterone relaxes blood vessels, Sarrel noted. This has obvious implications for the female genitalia. For both men and women, the events that take place during sexual arousal involve similar neurotransmitter and non-neurotransmitter mediated increases in pelvic blood flow and genital engorgement.   

Testosterone therapy for women has also been shown to be synergistic with statin drugs in the treatment of hypercholesterolemia, most notably demonstrating one of the few interventions that lower Lipoprotein (a) levels.   One caveat: Testosterone decreases HDL (high-density lipoprotein) cholesterol by 10%; those with low levels of HDL should think twice before taking it.(30)

Davis and Tran provide an excellent rationale for establishing treatment target levels. (33) Savvas and Watts in separate studies demonstrated the benefits of testosterone and retention of bone mineral density. (34,35) Davis suggested testosterone patches for menopausal women. (32) 

Miller studied 51 women in a double-blind investigation who suffered from an under-active pituitary gland, depriving their bodies of the relatively small amounts of testosterone women need.  Because all of the women had some form of pituitary disease, most were taking some type of supplemental estrogen; all were pre-menopausal and of reproductive age. Half the women were randomized to receive 300 micrograms of testosterone daily in the form of Intrinsa transdermal patches; the other half received look-alike placebo patches. The women were evaluated at regular monthly intervals for 12 months.  

After one year, dual x-ray absorptiometry revealed significantly improved bone mineral density in the testosterone group. For example, hip density improved by an average of nearly 1%, compared with a more than 1% loss in the placebo group (P=.023).  Muscle mass grew by an average of nearly 7%, compared with a 1.5% increase in the placebo group (P=.038). Fat mass did not significantly change in either group. Women in the treatment group reported significantly better overall mood (P=.029) and sexual function (P=.044), including increased arousal and overall better sexual experiences, per investigators.  

The dose of testosterone used in this study was just 6% of a standard male dose, the researchers noted.  Testosterone was well tolerated by the women, with a significant increase of acne in the testosterone group; neither had hirstuitism nor alopecia, the investigators said.  

The authors noted “the preparation used in this study caused local irritation in many subjects, severe enough in some women (6% of the total) to prompt discontinuation from the study. Most of the rashes were mild, all were local, and the majority of subjects who experienced them chose to remain in the study. The irritation was not likely caused by the testosterone itself because it was experienced by similar numbers of women in both groups.” 

While the benefits of testosterone therapy for testosterone-deficient men have been fairly well established, the benefits for testosterone-deficient women have been less clear, the authors said.  “This randomized, placebo-controlled protocol is the first to demonstrate increases in bone density and changes in body composition due to physiologic testosterone replacement in a group of women with severe androgen deficiency,” the authors said.  

“Moreover, this is the first study to show improvements in mood, sexual function, and quality of life in women with hypopituitarism receiving testosterone replacement therapy,” they added. (36) 

In 2004, Paoletti studied both male and female subjects.  He found lower testosterone levels were predictive for Alzheimer’s disease. Elevated SHBG was also associated with risk. Testosterone therapy lowered SHBG. (37) 

Hogervorst, Int J Ger Psy, 2003: Testosterone replacement associated with decline in APO-E4 levels in non-demented controls at high genetic risk.(38)

Female Sexual Dysfunction
Female Sexual Dysfunction (FSD), as defined by the International Consensus Conference Report published in the Journal of Urology in 2000, is a state of persistent or recurring reduction of sex drive, aversion to sexual activity, difficulty becoming aroused, decline in ability to reach orgasm or pain during sex. The National Health and Social Life Survey (Laumann, JAMA, 1999) stated approximately 43% of adult women in the United States report some symptoms consistent with FSD. These data closely resemble the reporting and incidence of erectile dysfunction in males, as reported in the Massachusetts Male Aging Study, described prior.   

In women, the most commonly reported symptom of FSD is diminished desire, with no clear-cut specific etiology that is most commonly seen. In males, the most common cause of erectile dysfunction has been shown the result of atherosclerotic blood vessel changes. There is a wider variety of descriptive symptomatology when discussing FSD. The key is discussing FSD in the context that the patient has noticed a change in her sexual habits or function, which causes distress.

 

Similar to erectile dysfunction in men, the list of FSD causes includes factors, such as general mood, desire (especially in association with stress, fatigue and depression), general health and hormonal factors. The most important step in improving FSD is first inquiring as to whether or not it is present. Males typically have a more “object related” relationship to their genitalia, which gives them a more direct avenue of bringing up sexual dysfunction in their patient-physician interactions.

When dealing with FSD, it is frequently incumbent upon the physician to initiate the discussion of the topic since many women do not spontaneously offer FSD as a complaint. Permission to discuss an issue can be therapeutic in and of itself. It is up to the individual practitioner to then decide upon the comfort level, regarding how involved in the psychological/psychosocial social issues and the specific counseling and other interventions s/he wishes to pursue. Interestingly, some reports have noted that merely by having a caregiver bring up the chance to discuss the issue of FSD can have significant therapeutic impact. Also, even with minimal expertise, being aware of local resources for proper referral is an important beneficial medical tool.   

With concerns related to the “mechanics” and hormonal changes contributing to FSD, an age management medicine provider can have a tremendous impact on treating and preventing FSD as a routine part of patient care.  When considering the possible etiology of FSD, there is much physiologic overlap with erectile dysfunction in men.  

The erectile dysfunction of diabetes in men has a clinical counterpart in women:  Elevated blood glucose levels are associated with elevated levels of Advanced Glycation End Products (AGE.) Exposure of blood vessel endothelium to AGE/Glucose complexes inhibits endothelium-dependent vasorelaxation by inhibiting endothelium nitric oxide synthase activity and responsiveness to nitric oxide. Both male and female blood vessels in the pelvic area are responsive to nitric oxide and show similar declines in responsiveness associated with AGE glucose levels. This finding has also been demonstrated to be reversible. (3)  

Nitric oxide directly effects capillary inflow to the vaginal mucosa, producing a transudative lubrication, vaginal smooth muscle relaxation that allows adaptation of the vagina for comfortable intercourse and clitoral engorgement, associated with enhancement of clitoral sensation and response to stimulation. Additionally, the pudendal nerve carries afferent signals to spinal nerve roots S2-3-4, increasing pelvic floor muscle tone and strength of muscle contraction. Elevated glucose levels decrease pelvic smooth muscle responsiveness to neurotransmitters. 

Interventions that enhance body image and body composition are also directly related to a woman’s feelings about her sexuality. Proper nutritional counseling and maintaining healthy activity levels are two of the three pillars of age management medicine, which contribute to the maintenance of optimal sexual function. Subjective reports of libido and sexual performance are affected by exercise and activity levels. Maintaining an active lifestyle is associated with reports of greater sexual satisfaction and performance. Once again, the literature demonstrates that nutrition is a broadly arcing item of clinical utility and cannot be separated from other interventions in age management medicine.  

Hormonal Aspects of Female Sexuality 

Estradiol (Estrogen) 

In the female sexual response, estrogen plays the greatest role in producing vaginal lubrication and genital blood flow. Changes brought about by surgical or naturally occurring menopause can have tremendous impact on female sexuality. Declines in estradiol are associated with thinning of the vaginal mucosa and atrophy of the vaginal wall smooth muscle cells. These findings are frequently associated with the clinical complaint of Dyspareunia.  

Decreased estradiol levels are associated with a decline in nerve transmission in tracts, associated with sexual response. Estradiol replacement studies have been shown to restore clitoral and vaginal vibration and pressure sensation thresholds to near premenopausal levels. Estradiol replacement therapy also has been shown to have endothelial-protective and vasodilatory effects, resulting in increases in vaginal, clitoral and urethral arterial blood flow, helping maintain normal sexual response and tissue integrity. There is a direct correlation between the presence of FSD and estradiol levels below 50 pg/mL.   

These findings related to estradiol level point out the contribution of objective therapeutic monitoring to ensure estrogen replacement therapy is being properly dosed and administered, giving the clinician an objective foundation for hormone modulation targets.   

Estradiol replacement helps maintain vaginal and clitoral nitric oxide production, vaginal mucosal thickness, pelvic capillary response; it is associated with a decline in vaginal wall cell apoptosis and vaginal wall cell death rates. (6) Additionally, estradiol replacement therapy can diminish the loss of what women describe as pleasurable nipple sensitivity, which can be associated with menopause.   

When a patient is considering estrogen replacement therapy, discussion of sexual symptoms should be part of the decision-making process and the information put forth in the context a patient’s signs, symptoms and expectations to help her make the most informed and individualized decisions possible. 

Testosterone

Testosterone is an under-appreciated hormone in female sexual function. Testosterone levels can decline at or before menopause, and often play a significant role in female sexuality. Women’s testosterone levels decline by approximately 50% between the ages of 20 to 40. Total testosterone levels less than 20 pg/dL are associated with declines in sexual arousal, genital sensation, libido and quality of orgasm. (7) There may be an accompanying diminishment in measures of well-being and loss of vaginal mucosal thickness. (3) Testosterone replacement therapy has been shown to increase levels of desire and frequency of seeking out sexual contact. (11) Testosterone replacement therapy is also associated with increases in pleasure and orgasm during sex.  

Braunstein studied the use of testosterone for the treatment of low sexual desire in surgically menopausal women (published in Menopause, 2003), showing a 30% increase in frequency of “total satisfying sexual activity” and an 81% increase versus pretreatment baseline. (45) Similar findings were reported by Davis in Efficacy and Safety of Testosterone Patches for the Treatment of Low Sexual Desire in Surgically Menopausal Women, published in Fertility and Sterility in 2003.  (32) 

A study Sarrel published in the Journal of Reproductive Medicine demonstrates testosterone’s dual role. He shows that in addition to improving sexual function, testosterone raises circulating levels of free estrogen in the bloodstream.  (46)  

For the purposes of this study, the Yale gynecologist enlisted 20 volunteers who were dissatisfied with hormone replacement therapy because their sex lives were deteriorating. He gave half of the group conventional hormone replacement (either estrogen alone or a combination of estrogen and progesterone) and added testosterone for the other half.   

The women taking testosterone reported “significant increases in sexual sensation and desire and more frequent intercourse after four weeks and again at eight weeks after starting therapy.”   

Sexual function improved. This occurred along with the increase in “free estrogen” from baseline. Interestingly, this occurred even though these same “free” estrogen levels were lower than those measured in the same women during their previous estrogen therapy. Although some trials of testosterone have not found any benefit, a number of other trials have also found testosterone enhances sexual activity, drive and enjoyment, Sarrel said.   

Here’s why women on estrogen might especially need testosterone: Most of a woman’s natural testosterone supply is already “bound” to a protein called sex hormone binding globulin, or SHBG. Only about 1% is bioavailable to act on tissues. Estrogen given alone triggers the production of more SHBG, which then binds up more testosterone.  

DHEA 

The body’s most abundant hormone DHEA is also the one whose levels fall most rapidly. DHEA replacement has been shown to increase libido with physiologic replacement. (12) Doses averaged 50mg per day. 

Other Products

There has been much discussion in the lay press regarding the possible utility of nitric oxide enhancing agents, such as Sildenafil, Vardenafil or Tadalafil, but no placebo controlled studies have demonstrated a significant or dependable improvement in female sexual response. (Basson, 2000, Obstetrics and Gynecology) (13) With its safety profile, if an individual woman has no contraindications to care, an individual trial may be worth considering, given the low incidence of intolerance in the same trials.  

Tibolone is a broadly acting synthetic steroid available in Europe, which binds to several different steroid receptors. In several trials, it has been shown to have little or no effect on enhancing female sexual response. But larger scale studies are being undertaken to try to differentiate any potential benefit of Tibolone vs. other bioidentical hormone interventions. (14, 15, 16) 

At present, bioidentical hormone modulation is still the intervention best supported by the medical literature with regard to optimizing female sexual response. 

Parting Notes On FSD
Finally, it is important to point out that all of the responses described in the literature regarding hormone modulation therapy take place within a physiologic context. No levels are taken above what is seen in normal premenopausal women. The specific aims of these therapies are to approximate those levels associated with optimal health and sexual response. 

The tools routinely used by the age management medicine caregiver to minimize markers of health risks have significant overlap with outcomes associated with quality of life measures. The benefits with regard to female sexual function serve to add to the positive impact these interventions can have in caring for our patients.

Synthetic versus Bioidentical HRT
Studies for or against the use of bioidentical hormones are greatly lacking.  The large pharmaceutical companies are against any such research because bioidentical hormones are compounded by pharmacists.  There is a bill before Congress, sponsored by Wyeth, to deny compounding pharmacists the right to compound hormones and sell them.  However, the following studies may assist in beginning to sort this out:

Staren found the conclusions of the WHI study may not apply to women taking other estrogen and progestin formulations. In vitro studies, epidemiologic surveys, and mostly, in vivo studies of human breast cancer cell proliferation show opposite effects when CEE plus MPA are compared with estradiol plus progesterone. (39) 

De Lignieres et al studied the risk of breast cancer with estradiol and a progestin other than MPA.  3175 postmenopausal women followed up for 8.9 years; 83% received exclusively or mostly a combination of transdermal estradiol gel and a progestin other than MPA.  Results were no increased risk of breast cancer (RR 0.98; 95% CI, 0.65 to 1.5) in the HRT users. (40) 

Stevenson JC et al conducted a randomized trial of effect of transdermal continuous combination hormone replacement therapy on cardiovascular risk markers.  The researchers found that transdermal continuous HRT had beneficial effects on vascular function and CAD risk markers.(41) 

Fournier, et al studied breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. This report from an ongoing French cohort study concluded the risk of breast cancer is slightly increased with a postmenopausal hormone therapy regimen consisting largely of transdermal estradiol combined with synthetic progestins but not when combined with progesterone. (42) 

More studies comparing the effects of bioidentical hormones and synthetic hormones are found on Slide14

For estradiol and progesterone replacement therapy, the goal is lowest effective dose. Estradiol (premenopausal peaks to 750 pg/ml): Therapy goal is 80-100 pg/ml. Topical therapy, typical starting dose 2.5 mg daily dose crème, 0.1 mg via patch. Progesterone (premenopausal peaks to 28 ng/ml): Goal of therapy 1-3 ng/ml. May be dosed orally, typical starting dose 50 mg po qhs.

For testosterone replacement therapy: Therapy goal is upper 50 percentile of premenopausal levels. 50-70 ng/dl total, 7-8.5 pg/ml free. Testosterone crème for women. There appears to be no appreciable conversion to DHT. QHS (QD) dosing.  Levels appear to follow shallow zero order curve rather than first order.  Delivered topically, initial dose is 2mg/day.  Example: 4mg/gm crème, ½ gram qhs. Testosterone appears to be well tolerated.  Side effects <1%: Acne, hirsutism, masculinization, mood change, male-pattern hair loss.

Note: Rapid subjective response

The Cornerstone of Care: Follow-Up

Follow-up labs are drawn after seven weeks of therapy. Once all markers are in target range, the evaluation period may be extended to 4 months for “items of interest.”

Compliance

One study showed that over-all, 96% of patients report their physician’s opinion was the deciding factor regarding whether or not they pursued ERT/HRT.

A study was conducted by Corrado to verify the compliance with hormone replacement therapy (HRT) over two years in a population of postmenopausal women in East Sicily. Patients starting hormonal therapy for the first time were enrolled in this study. A telephone survey was then conducted after 3, 6, 12 and 24 months; reasons for any discontinuation were recorded.

Results: Of the total 138 women who agreed to be enrolled in this prospective longitudinal study, 72 (52%) were still taking the treatment after 1 year and only 56 (41%) at the end of the study, although only three patients reported they had experienced no benefit. (43)

Type of work, surgical menopause and previous use of oral contraceptives were significantly statistically associated with better HRT compliance. Side effects and fear of breast cancer, which we maintain is exaggerated by women and their doctors, were the commonest reasons for early discontinuation of the hormonal treatment.