Hormone Modulation for Women

General Overview of the Normal Female Menstrual Cycle 

Any discussion regarding the manipulation of female hormone levels should first begin with a review of the physiology of the “normal” female cycle. We understand that this is a gross oversimplification, however it does provide for a brief overview for those of us that have not reviewed these concepts since medical school!   

The story actually begins with the female fetus in utero, however for our purposes we will fast forward to the relationship of the hypothalamic-pituitary axis and its relationship to follicle formation, ovulation, and the hormonal changes that result. We will then examine the effect that these hormones have on the endometrium and how that impacts the decisions we subsequently make regarding HORMONE REPLACEMENT THERAPY regimens and strategies.  

In the reproductive age female, the process begins with the hypothalamus releasing gonadotrophin-releasing hormone (GnRH) which in turns stimulates the release of follicle stimulating hormone and luteinizing hormone in a pulsatile pattern from the pituitary gland. Just as the name indicates, the FSH will stimulate follicular development eventually leading to the development of a dominant follicle. This early phase of the menstrual cycle is thus referred to as the follicular phase. During this follicular phase one sees rising estradiol levels. In turn these estradiol levels act upon the endometrium to stimulate growth, preparing it for implantation, the “proliferative” endometrium. It is beyond the scope of this discussion (and frankly for our purposes-unnecessary) to go into great detail as to the histological changes that define each endometrial phase.  

At midcycle, the pituitary releases a surge of LH, to induce ovulation. After rupture of the dominant follicle and expulsion of the ovum, the follicle involutes and is known as the corpus luteum. This corpus luteum is hormonally active, secreting progesterone and is necessary for the maintenance of pregnancy. Thus the later half of the menstrual cycle is termed the “luteal” phase. It is obviously characterized by increasing progesterone levels which matures the endometrium and sustains the pregnancy. If the ovum is not fertilized, the corpus luteum has a fixed life span of 14 days. It is the fall in both the estradiol and progesterone levels that is responsible for the vascular changes that result in a shedding of the endometrial lining and withdrawal bleeding.  

The following chart nicely summarized these changes at the various levels:  Slide01 

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

Menopause

The average American woman’s life expectancy currently exceeds 81 years of age. Therefore, most women can expect to live more than one-third of their lives well beyond their childbearing years. Today menopause is no longer the hush-hush topic of our grandmothers’ generation. Both the non-medical and medical communities throughout our 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. The 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 early to mid-50s. 

In 2001, Stages and Reproductive Aging Workshop (STRAW) created a far more detailed staging and nomenclature system. STRAW was jointly sponsored by the American Society for Reproductive Medicine, National Institute on Aging,  National Institute of Child Health and Human Development and North American Menopause Society. The purpose of this model was to better define the menopausal transition, its duration and physiologic effects.  

The stages range from -5 to +2 with 0 being the final menstrual period. The various stages are defined by the regularity of menses and endocrine changes seen at various points within that stage. 1  Slide02

In addition to diminished levels of estrogen and progesterone, testosterone (also produced in the ovaries) and growth hormone (produced by the anterior pituitary) are reduced during menopause. As the levels of all of these key hormones diminish, profound changes begin occurring with growth and metabolism that affect the 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, of course, but in general 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 that 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 a hot flash, a sudden sensation of intense heat. Some women actually experience dermatologic changes, such as breaking out in red blotches on their chest, back and/or arms. Some sweat profusely; many also experience cold and shivering until their bodies readjust. This can frequently occur during the night resulting in insomnia, which is a common complaint among menopausal women.  

Some women experience an “aura” prior to the onset of a hot flash, which may include tingling, anxiety and a pressure like sensation in their head. 2  

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; 1 out of 20 women has persistent symptoms.  Twenty percent of women can have symptoms for up to 15 years!

Vasomotor symptoms have long been thought to be a nuisance to be tolerated, but of little real clinical significance. However, studies have demonstrated they are associated with sleep disturbances, impaired quality of life and depressed mood. 3  

While the exact pathophysiology is not fully understood, they are thought to be the result of changes in the hypothalamic thermoregulatory set-point that occur with the endocrine changes of ovarian failure. The neurotransmitters serotonin and norepinephrine, as well as estrogen acting as a neuromodulator, are known to have input to this center. As estrogen levels decline, modulations occur in serotonin and norepinephrine synthesis, release, degradation, reuptake and receptor activity. 4  

In support of this postulated mechanism, a new nonhormonal drug, desvenlafaxine succinate, has been shown in recent trials to be safe and effective in reducing the incidence and severity of vasomotor complaints. The drug, which is not yet approved by the FDA, works by inhibiting serotonin and norepinephrine reuptake (SNRI).5 The  approved antidepressant—venlafaxine, which works by the same basic mechanism—has shown conflicting results in studies
thus far. 6

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 patterns of change in ovarian, pituitary and hypothalamic function

• body mass index

• health behaviors (smoking, nutrient intake, exercise/activity patterns, alcoholic beverages and caffeine)

• race and ethnicity

• socioeconomic status (indicated by education, income, occupation and perceived income adequacy)

• personal characteristics (affect, self-consciousness and attitudes toward menopause and aging) 7

Women with high anxiety were nearly five times more likely to report hot flashes.  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% were in the early transition stage, and 20% reached the late menopausal transition or were postmenopausal.8 

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 the occurrence of hot flashes and 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. 8 

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; atrophy usually begins to improve within as little as two weeks of instituting therapy with good control achieved by the one to three-month mark. 7  

Loss  Of Libido
Rarely discussed, the loss of sex drive is another by-product of the menopausal experience. Women generally have 1/10th to 1/20th of the testosterone levels that men have. The waning of premenopausal levels of testosterone and DHEA can be a contributing factor to a woman’s loss of desire for sexual intercourse.9 

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, which is strongly associated with menopause. There is no consensus as to just how much lifestyle, alteration of family roles, changing social networks and emptying of the nest contribute to the emotional changes of post-menopausal women. It is clear, however, that hormonal decline is a major contributor to this emotional instability. 

Osteoporosis

Bone mineral density and risk for osteoporosis is 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.10  

Of the more than two million American men with osteoporosis, one out of every four over 50 will have an osteoporosis-related fracture in his lifetime.8 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.10 

Slide03

Osteoporosis is primarily a manifestation of estrogen insufficiency; however, testosterone, progesterone, DHEA and growth hormone also play a role in maintenance of bone density.
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 against bone loss. 

Weight-bearing exercise promotes bone mineral density retention and, for 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, in much 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 these are 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 these fat deposits, eventually resulting in the occlusion of the vessel lumen. Early recognition, lifestyle changes and hormone modulation (bioequivalent and when taken by the proper delivery route) have shown to be very effective in reducing the incidence and severity of cardiovascular disease in post-menopausal women when initiated early in the climacteric. 

A prospective analysis examining the relationship between hormone replacement therapy (HRT) and coronary heart disease (CHD) was published in the Journal of Women’s Health, 2006. The study examined the relation of HRT to CHD, according to the timing of initiation of therapy and time since onset of menopause. The results demonstrated that women beginning HRT near menopause had a significantly reduced risk of CHD. The authors concluded that the “data support the possibility that timing of HRT initiation in relation to menopause onset or to age might influence coronary risk.” 11 

A secondary analysis of data from the Women’s Health Initiative published in JAMA, 2007 also concluded this: “Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause.” However, they did point out that the trend did not meet their criteria for statistical significance. 12 

Sleep Disorders In Menopause

We have long known that menopausal females complain of insomnia—with difficulties of falling asleep and staying asleep. It has been believed that the difficulty staying asleep was related to vasomotor symptoms, i.e. night sweats or perhaps the terminal insomnia that is seen with depression.  

A study published in Menopause, 2007 demonstrated that the major predictors of reduced sleep efficiency were related to primary sleep disorders: apnea and periodic limb movements (PLM).  In the study, 53% of the women had apnea, restless legs or both. The best predictors of objective sleep quality were number of apneic events, PLMs and arousals as determined by polysomnography. Hot flashes were associated with subjectively decreased quality of sleep.13

These findings are consistent with a study from the Journal of American Board of Family Medicine Mar-Apr 2008. Mold, JW et al. concluded that subjective night sweats are associated with a variety of subjective sleep-related symptoms. There was no evidence for an association between subjective night sweats and objective evidence of specific sleep disorders.14

Risk Factors for Symptoms

There are modifiable risk factors for increased symptoms of menopause, including diet, weight, cigarette smoking, exercise patterns, depression and anxiety. The non-modifiable risk factors are race, family history and menopause at a 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-ranging 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 after. At age 60, an average unsupplemented female will have lower estrogen levels than a similarly aged man.2 

Physiologic effects of estrogens include maintenance of uterine and breast tissue, significant effects on vaginal mucosal thickness and lubrication, as well as aiding in maintaining proper vaginal flora. Additionally, estrogen is associated with retention of quality 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 associated with favorable lipid profiles, vasodilation and the inhibition of the development and progression of atherosclerotic lesions.16 Additionally, maintenance of estrogen is also associated with improved lymphocyte function and the continued expression of steroid receptors.17  

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.20, 21  In addition, maintained estrogen levels have a strong correlation with significant reductions in risk for colon cancer and macular degeneration.18, 19 

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. Large randomized clinical trials (RCT) including data from both the WHI and the HERS trials demonstrated up to a 21% reduction in incident-treated diabetes or 15 fewer cases per 10,000 women per year of therapy. 22  These benefits are also demonstrated by the association of estrogen levels and decreased central adiposity. Whether the two are related is a promising area for future research.  

Other studies have shown the correlation between estrogen levels and quality of sleep, retention of skin elasticity 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) that 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 as well as 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 module, were performed using oral conjugated equine estrogens and synthetic progestins. CEE contains forms of biologically active estrogens that are not natural to humans. In addition, the oral forms, as we will discuss 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 (CAD) accounts for up to 50% 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 having been found 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 also is correlated with lower levels of markers of lipid oxidation. Tissue studies have demonstrated greater endothelial integrity and lower likelihood of plaque rupture in women with retained estrogen levels.22 

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

Regarding the impact of ERT/HRT on prevention of CAD, the Wenger meta analysis of the 30 largest hormone replacement studies showed a range of 35%-50% reduction in risk. ERT was judged equivalent to HRT, with the PEPI study slightly favoring HRT. Considering that one in two women will die from CAD, this is a profound reduction in mortality risk. 23 

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. (Remember: The original analysis of the WHI data did not take into account the timing of therapy initiation.) 

Women taking unopposed estrogen, however, demonstrated a significant slowing of subclinical atherosclerosis compared with non-HRT and estrogen plus progestin.24

It is felt that the synthetic forms of progestins used in a vast majority of studies may actually have deleterious cardiac effects. 

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 CAD.  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 year eight 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 and no benefit of HRT on cognitive function was noted. 22,24  Slide04  Slide05

The Women’s Health Initiative (WHI) included two large clinical trials that evaluated whether hormone therapy with estrogen reduces the risk of CAD in postmenopausal women. In the part of the study designed to test estrogen therapy alone, 10,739 women aged 50 to 79 years who had undergone hysterectomy were assigned to take either oral conjugated equine estrogens—a mix of several estrogens—or a placebo. Though researchers had planned to study the women for 8.5 years, the estrogen-only trial was stopped in March 2004 after only 6.8 years because the hormone treatment appeared to increase the risk of stroke. ²⁵ Slide06  Slide07

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 years.  

Among these women (a total of 1,396) who were aged 50 to 59 years at the start of the study, there was no significant reduction in myocardial infarction or coronary death among those taking estrogen. “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.(2006) and Humphries (2007) conducted an extensive review of the research and reports on HRT and the cardiovascular system.  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 towards harm.26  Slide08

Viscoli et al. in the WEST studied the use of HRT in women who had a TIA or ischemic stroke.  He concluded that estradiol does not reduce mortality or the recurrence of stroke in postmenopausal women with cerebrovascular disease. This therapy should not be prescribed for the secondary prevention of cerebrovascular disease.19  Slide09

New analysis of data from the Nurses’ Health study and published in the April 28, 2008 issue of the Archives of Internal Medicine, demonstrated an increased risk of stroke in HRT users regardless of the timing in initiation of therapy. This risk was dose dependent with a higher risk in Premarin only treated patients as opposed to those on CEE and MPA. The relative risk for those women on lower dose CEE (0.3mg daily) was actually lower than that of the control population. 27 

HRT & Deep Vein Thrombosis

Risk for development of deep venous thrombosis (DVT) has been addressed by several studies. The data preceding the HERS study demonstrated a range of two- to four-fold increase in risk associated with ERT/HRT. The HERS study delineated similar findings, describing a three-fold increase in risk. The HERS study, however, was one of the first to attempt to evaluate which subjects within a cohort were at risk; researchers 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 (aside from inherited thrombophilias).   

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.  A health maintenance program that addresses the potential benefits of low dose aspirin therapy obviates concerns regarding any increase in DVT incidence in patients on ERT/HRT.25

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 it improved 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%-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.28    Slide10

Dr. Dennis T. Villareal—from Washington University School of Medicine in St. Louis—and colleagues assessed the bone-related outcomes of 67 women with mild to moderate physical frailty, 75 years of age or older who were randomized to receive HRT or placebo for nine 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.” 29. 

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.   

For women who are unable to undertake ERT/HRT, the use of Selective Estrogen Receptor Modulators (SERMs – Tamoxifen, Raloxifene) may be an alternative that still confers bone and cardiac benefits with no associated ERT/HRT risk. These modulators do not, however, ameliorate the symptoms of vasomotor instability or other subjective menopausal complaints.30

HRT & Cancer

Uterine Cancer
There is agreement in the literature regarding the risk of uterine cancer with 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 that are 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. 31 

This increased risk does not appear in association with combined estrogen/progesterone therapy (HRT).  The use of progesterone prevents the hyperproliferative effects of estrogen on the endometrium. This data is the cornerstone of the rationale for using combined hormone replacement rather than monotherapy. 31 

A prospective three-year clinical study was conducted by Yang et al. to examine 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 that HRT does increase uterine fibroid volume statistically. However, its effect appears in the initial 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. 32 

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.  

With respect to breast cancer, various studies have demonstrated relative risk ratios varying from 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% at baseline to 4.1% or 4.6% at maximum. A 30% increase in the relative risk is actually an 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 that experiences an intervention that increases life span would most likely experience an increase of cancer incidence, given that a portion of the population that would have died otherwise would instead be alive to develop cancer later. 

As a comparison, risk for death from CAD is reported to be as high as 50%. ERT/HRT may reduce 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 that 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; and 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) 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 who received HRT had one half of the annual mortality rate of their untreated counterparts. 33, 34  

Daling, JR found 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. 35 Another study by Pappo found that breast tumors in HRT users vs. nonusers were of a significantly lower stage and grade and accounted for a higher number of favorable histological types, but all other parameters were similar in the two groups. 36 

In the Breast Cancer Detection Demonstration Project (BCDDP; 46,000 pts.), ERT 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. Of note, 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 3-9 years. The Iowa Women’s health Study (IWHS, 37,000 pts.) showed similar findings.40 

In the Creasman/Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) analysis, the conclusions were that in total, studies ranged from no increase in relative risk to an upper limit of increased risk to an RR of 1.14. 23  Slide11

The UK Million Women Study confirmed a small increase in risk for breast cancer in association with estrogen-only products.  Increased risk of breast cancer in association with the use of combined estrogen plus a synthetic progestin (both continuous and sequential regimens) was substantially higher than estrogen only.  An increase in risk for breast cancer becomes apparent within one to two years of starting therapy, irrespective of the type of HRT used.  The risk of breast cancer begins to decline when HRT is stopped; by five years, risk reaches the same level as women who have never taken HRT. This was a questionnaire study, lending itself to a bias toward pathology.  Healthy, happy people don’t reply; therefore, it was probably a statistically invalid study.37   Slide12

Like the WHI study, the results of the Nurses Health Study (NHS) found no statistically significant increased breast cancer risk when estrogen therapy was used for less than ten years, wrote Dr. Chen and Harvard researchers.  However, they 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. 38 

The NHS, was a prospective cohort study, including postmenopausal women who had had a hysterectomy, eventually including 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, so that 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).  39 

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 who 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, the researchers said, 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.  

There might be other confounders that separate out the long-term users, the researchers wrote, although they noted that they controlled for most of the known breast cancer risk factors. Finally, Dr. Chen wrote, the increase in breast cancer risk with increasing duration of estrogen therapy suggests “a true biologic relationship.” 38 

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,” the investigators advised.  

Interestingly, a retrospective study of postmenopausal females who were on testosterone in addition to estrogen and a progestin demonstrated a breast cancer rate substantially less than those on estrogen and progestin therapy alone. The rate for estrogen/progestin and testosterone users was 293 per 100,000 woman-years in this study. In contrast, the WHI study results had a rate of 380 per 100,000 woman-years; the “Million Women” Study had a rate of 521 per 100,000 woman-years. Theoretically, ovarian androgens may protect mammary epithelial cells from excessive estrogenic stimulation, and protect against breast cancer. Clearly, more research is needed on this topic.26  

In conclusion, the data is confusing at best and conflicting at worst.  While there does seem to be a tendency toward a slight increase in relative risk (especially with long-term use), the clinical significance of this increased risk must be discussed with the individual patient and taken into account when the decision is made to offer HRT to a given patient.  Slide13

As a prophylactic measure, one may consider the addition of Indole 3 Carbinol as an adjunct to HRT regimens. As a naturally occurring phytonutrient found in cruciferous vegetables, it may block the formation of 16 alpha hydroxy estrones that have been associated with an increased risk of breast cancer. 

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 and 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 and without prescreening certainly some women 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 and 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 a WHI analysis in October 2003. He concluded that 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 percent 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. 16 

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 is not statistically significant even at the nominal level. For several decades, data from univariate analysis that have 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.39 

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

Putting Everything Into Perspective – Slide14

HRT & Dementia

Strong data exist relating low estrogen levels and risk for development of dementia with equally strong correlations between having received hormone replacement therapy and reduced risk for, or delayed onset of, dementia. Tang found that hormone replacement delayed onset of dementia and showed significant over-all reduction in total risk.  Schmidt, in 2006 reported that 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. ⁴¹ 

Manly reported an association between low estrogen levels and the development of Alzheimer’s disease.  Waring found hormone replacement therapy was associated with a significantly reduced risk of Alzheimer’s disease. ²¹ 

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 And Its Effect On IGF-1 Levels

The route of delivery of estrogens can have a significant impact on other variables and hormone levels as well.42 

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 that 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.  43   
The effects on LH levels and BMD did not vary with route of delivery.45  

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 that occur with oral estrogen preparations.45 

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.46 

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. 44

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 seen on estrogen replacement therapy alone is negated. 

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. They have also 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. Because synthetic progestins are now widely used in postmenopausal hormone therapy, it is critically important that 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.   

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 that 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.  ⁴⁷  

At this point a brief reminder is in order. The medroxyprogesterone acetate (MPA) that has traditionally been used and studied in HRT regimens is a synthetic progestin, not progesterone. 

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 found no increased risk of breast cancer (RR 0.98; 95% CI, 0.65 to 1.5) in the HRT users.48

Staren noted 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.49 

Sustained progesterone may be inhibitory to breast cancer cell lines and have been demonstrated to have antiproliferative in vitro effects.  

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

Natural progesterone therapy is associated with improved self-report of mood and scores on mood evaluation testing. It is a natural anxiolytic that may be associated with improvements in sleep onset and duration. Natural progesterone is also a mild diuretic. 

Continuous-Sequential Estrogen-Progesterone Therapy (CS-EPT) Vs. 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) needs to be elucidated.  A review of the literature does not clearly demonstrate superiority of one method over another.50 

While Stevenson et al. concluded that 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, other studies have suggested otherwise.51  

In a 2001 review of HRT dosing regimens comparing continuous versus cyclical therapies, Shoupe concluded that “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.”52 

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.”53 

The choice is best made on a case-by-case basis, with a thorough discussion between physician and patient regarding the pros vs. cons of each regimen.  

The Future of Hormone Replacement Therapy and Bioequivalent Hormones

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.  Studies comparing the effects of bioidentical hormones and synthetic hormones are found on Slide15

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.  

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 benefits while minimizing any undesirable effects. As these dosing protocols are evaluated, it may trend dosing choices downward and allow further reduction in patient risk while maintaining the benefits. 

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 and poor glucose control.  Declines in tesotosterone levels occur premenopausally with up to a 50 % decrease in levels between 20 and 50 years of age.   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 as those seen in men. Improvement in the following areas is seen: cognition, libido, sexual responsiveness, body composition, preservation of lean muscle mass, improved glucose metabolism and lipid profile. Other reviews point out the benefit of testosterone therapy for controlling vasomotor symptoms, mood and bone density. 54, 55  

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 though: Testosterone decreases HDL (high-density lipoprotein) cholesterol by 10%, so those with low levels of HDL should think twice before taking it.  54  

Davis and Tran 56 provide an excellent rationale for establishing treatment target levels.  Savvas 45 and Watts 46 in separate studies demonstrated the benefits of testosterone and retention
of bone mineral density. Davis suggested testosterone patches for menopausal women.66

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 that women need.  Because all of the women had some form of pituitary disease, most were taking some type of supplemental estrogen and all were premenopausal 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.  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, but neither hirstutism 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. 57

Paoletti in 2004 studied both male and female subjects.  He found that lower testosterone levels were predictive for Alzheimer’s Dz. Elevated SHBG was also associated with risk. Testosterone therapy lowered SHBG. 58

Female Sexual Dysfunction

Female Sexual Dysfunction (FSD), as defined by the International Consensus Conference Report published in the Journal of Urology in 2000¹, is described as 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)67 reported that 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 (ED) in males, as reported in the Massachusetts Male Aging Study described in our previous discussion.   

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

Similar to ED in men, the list of causes of FSD 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, as 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 their comfort level, regarding how involved in the psychological/psychosocial social issues and the specific counseling and other interventions s/he would want 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 that contribute 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 ED in men.  

The ED 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 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, which is 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 enhancing 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 contributes to the maintenance of optimal sexual function. We know that 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, we are shown from the literature 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 that result 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 ERT is being properly dosed and administered and give 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 and is associated with a decline in vaginal wall cell apoptosis and vaginal wall cell death rates.²⁵  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 of the patient’s signs, symptoms and expectations to help the patient make the most informed and individualized decisions possible.  

Testosterone

Testosterone has been an under-appreciated hormone in female sexual function. As we have discussed, testosterone levels decline even prior to menopause and often play a significant role in waning female sexual desire and responsiveness. Women’s testosterone levels decline by approximately 50% between the ages of 20-50. Total testosterone levels less than 20 pg/dL are associated with declines in sexual arousal, genital sensation, libido and quality of orgasm.⁶¹ There may be an accompanying diminishment in measures of well-being and loss of vaginal mucosal thickness.⁵⁵ Testosterone replacement therapy has been shown to increase levels of desire and frequency of seeking out sexual contact.⁵⁵ Testosterone replacement therapy is also associated with increases in pleasure and orgasm during sex. 64 

Bramstein studied the use of testosterone for the treatment of low sexual desire (P=.044)—including increased arousal and overall better sexual experiences, the investigators said—in surgically menopausal women (published in Menopause, 2003). Findings showed a 30% increase in frequency of “total satisfying sexual activity” and an 81% increase versus pretreatment baseline. Davis reported similar findings in Efficacy and Safety of Testosterone Patches for the Treatment of Low Sexual Desire in Surgically Menopausal Women, published in Fertility and Sterility in 2003.64    

Reviews by Davis, SR, Burd ID and Sherwin, BB looked at the benefits of testosterone supplementation with regard to libido, sexual responsiveness and maintenance of healthy genital tissue.61 62 Reports by Sarrel, P and Gelfand, MM relate similar findings from clinical studies.54 55   

Sarrel found that testosterone did not constrict blood flow to either the fingertips or to the 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 arteries have also found testosterone relaxes blood vessels, Sarrel noted. 54 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.   

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.    

For the purposes of this study, Dr. Sarrel, a 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 4 weeks and again at 8 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. 68  

Women on estrogen might especially need testosterone because most of a woman’s  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, thereby decreasing the amount of free or bioavailable testosterone.  

A study examining the use of testosterone in premenopausal females with low serum free testosterone levels was published in the 2008 Annals of Internal Medicine. 61 The researchers concluded that daily transdermal therapy improved self-reported sexual satisfaction in younger women with previously reduced libido. 

Transdermal delivery systems for testosterone are the optimal route for females. Oral forms of testosterone have a potential for hepatotoxicity and should be avoided.  Slide16

DHEA 

The body’s most abundant hormone DHEA is also the one whose levels fall most rapidly. DHEA levels are at their peak during young adulthood, i.e. early 20s, declining by a rate of 10%-20% per decade until the age of 80 years when they reach their nadir.  

DHEA replacement has been shown to increase libido ⁵ with physiologic replacement. Doses averaged 50mg per day. 

Most women are able to tolerate DHEA replacement without significant adverse side affects. The side effects most commonly seen if they do occur are increased oiliness of the skin and acne. Rarely, more obvious andronergic effects such as hirstutism or hair loss occur. 

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, 200, Obstetrics and Gynecology)⁶⁹. Given 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 that 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.^{2, 4, 6}  

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

As a final point, 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 that are 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. Slide17

Clinical Application

Before beginning hormone modulation for a patient, a complete physical must be done.  Lab work needs to include a premenopause/perimenopause/menopause Lab Panel:

DHEA Sulfate
Estradiol
FSH
Progesterone
IGF-1
Testosterone
          Total Testosterone
          Free Testosterone
          %Free
Thyroid Panel 
          Free T3
          Free T4
          TSH

Dosing & Delivery 
Slide17
For estradiol and progesterone replacement therapy, the goal is lowest effective dose.
Estradiol (premenopausal peaks to 750 pg/ml): Goal of therapy 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, goal of therapy 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 six to eight weeks of therapy. Once all markers are in target range, may extend evaluation period to q 4 months for “items of interest.” 

Compliance

One study showed that over-all, 96% of patients report that their physician’s opinion was the deciding factor regarding their decision whether or not to pursue 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 and the reasons for any discontinuation were recorded. Of a total of 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 that 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 the women and their doctors, were the commonest reasons for early discontinuation of the hormonal treatment. 

References

Post Test