Hormone Replacement Therapy

What do low sex drive, memory loss, and problems sleeping have in common? Is hormone replacement therapy the answer? Maryanne wrote a paper examining several research studies recently; read on, you may be surprised!

Hormone Replacement Therapy: The Effects of Testosterone on Perimenopausal Women

Maryanne Comaroto

Dominican University of California

Everyone is influenced by hormones in every aspect of our lives; they influence our health, behavior and social interactions.

Hormones are chemicals released into the bloodstream that interact with receptors on cells elsewhere in the body (A. Gharib, lecture, 2013). How this works is, a chemical is released in one part of the body, traveling various distances to another part of the body that has the correct receptors for it to bind to, ultimately altering the function of those cells (A. Gharib, lecture, 2013). There are 3 main chemical messaging systems in the body:

  • neurotransmitters, the most studied of the three, are specialized proteins that rapidly transmit an electrical signal (using one of over 50,000 available connections) sent over small distances in the brain, via long extensions called axons;
  • pheromones are a relatively slower process, specializing in transmitting signals over extremely long distances via a person’s vomeronasal organ (holes in the lower part of the nose designed to sense such signals), used for detecting potential mates; and
  • hormones, which are a kind of intermediate mechanism which, for example, helps maintain internal balance, or homeostasis. They can have long-lasting effects, some of which can last up to an entire lifetime, such as fetal development and gender determination (A. Gharib, lecture, 2013). Interestingly, some hormones are also neurotransmitters, depending on their mode of delivery; for example, epinephrine (adrenaline) can be released from a nerve terminal or from the endocrine system as a hormone (A. Gharib, lecture, 2013).

Hormones are an evolutionary mechanism found in all kinds of species, including plants, and are important for a variety of reasons, such as helping to maintain our survival drives; maintaining our internal homeostasis; organizing structures of the brain and body and, at different stages of life, our redundant systems, such as growth; and altering our mind and behavior (A. Gharib, lecture, 2013). The study of hormones is intrinsically interesting, as people are constantly actively manipulating hormones in themselves, and these small amounts of hormones can make significant thought and behavioral changes (A. Gharib, lecture, 2013).

Aristotle was the first to observe behavioral differences regarding hormones and behavior, noticing that boys with lower hormone levels became less aggressive and less interested in sex. Later, in the mid-1800s, A.A. Berthold introduced the world to the idea, and the study of hormones became known as Endocrinology (A. Gharib, lecture, 2013). Since then, science has identified several categories of hormones, among them growth, stress, and sex hormones. Testosterone is considered a sex hormone, and its effects have been observed since the beginning of recorded history; namely, observing what happened when young boys were castrated (A. Gharib, lecture, 2013). The production and effects of testosterone in women is less well-known (Rosick, 2004). This paper will investigate the role of testosterone as it relates to Hormone Replacement Therapy, and its effects on perimenopausal and postmenopausal women.

Testosterone is considered an androgenic hormone responsible for the development and maintenance of masculine characteristics, and is secreted in small amounts by the ovaries and adrenal cortex in females, and in larger amounts by the testes in males. Androgens in women either derive from peripheral conversion of the adrenal sex steroid precursor dehydroepiandrosterone or from direct ovarian production, towards active androgens (Arlt, 2005). Research has established important physiological effects of testosterone in women. “Testosterone acts directly via androgen receptors throughout the body, including in areas such as the brain, particularly the hypothalamus and amygdala; and at peripheral sites including bone, breast, skin, skeletal muscle, and adipose, vascular, and genital tissues” (Somboonporn, 2010).

Androgens are said to influence bone density, muscle strength, sexual desire, energy, mood, and psychological well-being. Research has also found cholesterol, which is obtained from the diet, to be the building block for androgens (Tan, 2005). Androgens in women include testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione 5-alpha-dihydrotestosterone (DHT). Among the androgenic steroids, testosterone and DHT are reported to have the most biological activity. Androgens work on receptors and multiple organ systems; for example, the limbic system and hypothalamus are influenced by androgens, thusly affecting memory and mood (Tan, 2005).

Perimenopause (PM), also called menopausal transition, refers to the period of time when a woman’s body begins its natural transition towards menopause, or permanent infertility. A woman who has gone through 12 consecutive months without a period has officially reached menopause. Women begin PM at different ages, typically in their 40s and, in some cases, as early as their 30s. Signs associated with PM include menstrual irregularity (shorter or longer periods) and various menopause-like symptoms such as hot flashes, vaginal dryness, and problems with sleeping. These symptoms occur primarily as a result of the fluctuation of the main female hormone, estrogen. Rising and falling levels of the hormone progesterone has also been linked to perimenopause and its symptoms (Mayo Clinic, 2013). Androgen insufficiency has been suggested to be associated with persistent fatigue, diminished sense of well-being, changes in sexual function, and depressed mood, as well as certain memory functions, sleep, bone-density loss, and low muscle strength (Gotmar et al., 2008).

Some experts argue most women do not need treatment of menopausal symptoms: “Some women find that their symptoms go away by themselves, and some women just don't find the symptoms very uncomfortable” (U.S. Department of Health and Human Services, 2013).

Hormone Replacement Therapy (HT) has been widely used for controlling perimenopausal and postmenopausal symptoms, as well as for the management and prevention of dementia, cardiovascular disease, and osteoporosis in older women (Majoribanks et al., 2012). There have been many changes and much conflict since the 1990s: The use of HT has declined, women have stopped using HT without consulting with their health-care providers, many women are denied HT who need it, and others are resorting to alternative therapies with little information about their efficacy (Halloway, 2010). Alternative treatments available for perimenopausal and postmenopausal symptoms include pharmaceutical supplements such as bioidentical hormone replacement, or manmade hormones that are the same as the ones the body makes; nutraceuticals, or foods and supplements containing naturally derived phytoestrogen; and lifestyle changes such as eating healthily, maintaining an ideal weight, exercising, and practicing stress-reduction techniques. All these have been associated with reduction in mild to extreme menopausal symptoms (U.S. Department of Health and Human Services, 2013).

Experts agree that clinical research on perimenopuse (PM) remains limited, forcing health care providers to rely on their own clinical experience and findings from postmenopausal women when attempting to manage PM symptoms (Frackiewicz & Cutler, 2000). Other research suggests that in recent years there has been a dramatic expansion in the range of licensed hormone replacement therapy (HT) regimens, and that it is more and more difficult for dedicated menopause experts to keep up (Sturdee, 2000).

Estrogen and progesterone have been the most common hormones involved in HT. The sex steroid, testosterone, has also been found to have many positive and protective effects on the brain. While levels of testosterone are naturally low in women as compared to men, small differences in testosterone levels can have quite an impact on bioavailable estrogens (Hogervorst, 2013).

Gotmar et al. (2008) investigated symptoms in perimenopausal and postmenopausal women in relation to testosterone concentrations. Prior research cited by the authors included female sexual dysfunction and its relationship to low androgen levels, and therapies combining androgen with testosterone to increase libido. Associations between testosterone concentrations and fat distribution (waist/hip ratio, or WHR), and the role of memory function and testosterone levels was explored. Additional prior research yielded varying results regarding when and how much total testosterone, free testosterone, and Sex Hormone Binding Globulin (SHBG) changed due to menopausal transition. The authors noted that men’s testosterone levels decline in age, which led them to hypothesize that women’s testosterone deficiency symptoms may be associated with low androgen concentrations. The authors aimed to explain apparent links between androgens and symptoms as well as symptoms attributed to low-androgen influences in perimenopausal women.

Participants included (n=6908) women; mean age was 56.4 years of age, born in Lund, Sweden, between 1935-1945. Participants were invited via a population register to participate in a program that included a physical examination, a questionnaire, and hormone measurements. The population was divided into three groups based on their menopausal status: PM, premenopausal; PMT, women on HRT (oral estrogen use); and PMO, postmenopausal women without HRT. The definition of menopause was 12 months bleeding (period) free. Additional analysis included education, degree of working, and physical activity.

The authors’ results showed PMT women experienced a higher degree of hot flashes than PM and PMO women. PMO women reported vaginal dryness more often that the other groups. Total testosterone levels were lower in the PMT women than in the other groups. PMT women were shown to have had higher levels of SHBG than the other groups, and PMO had lower SHBG than the PM women. Free testosterone (FTI) was lower in the PMT group than the other groups and estradiol levels were highest in the premenopausal women, whereas PMT had higher levels than the PMO women. BMI and WHR were also higher in postmenopausal women without HRT. Sexual well-being, health, and sleep were found to be significantly better in the group than the PMT or PMO group, but sexual well-being was better in the PMT group than in the PMO group. The PMT group reported lower energy, mood, and memory scores than the PM and PMO group. Women with current hot flashes had higher levels of total testosterone than women without hot flashes. More symptomatic women had overall higher levels of FTI compared to women without symptoms. Hormone concentrations in women without hot flashes at the moment, excluding effects of HRT, were not included in this analysis.

The authors reported total testosterone concentrations were lower in women using HRT (ingesting oral estrogens) compared to the other women in their study. They asserted this may have been due to consequences of a decreased gonadotropin drive. No differences were found in total testosterone concentration between PM and PMO women. Women who had hot flashes were shown to have had higher levels of FTI and total testosterone, but lower estradiol levels. Weak correlations were found with women’s FTI, total testosterone, and quality of life. Memory and energy, however, were significantly correlated with total testosterone. FTI and total testosterone showed no correlations with health, sleep, and sexual well-being. In summary, while the authors found that lower testosterone concentrations were associated with certain aspects of lower quality of life in perimenopausal women, the significant differences in androgens were said to be small and the biological relevance questionable. They concluded that there must be factors other than decrements in sex hormones that contribute to perimenopausal symptoms. Suggestions for further research included exploring the role androgens play, and the causes and mechanisms that explain the complex symptoms related to the PM transition.

Braunstein, Reitz, Buch, Schnell, & Caulfield (2011) investigated testosterone reference ranges in normally cycling healthy premenopausal women. The goal of their research was to determine the reference ranges for serum testosterone and sex hormone-binding globulin (SHBG) in premenopausal women with normal menstrual cycles. The authors asserted that there are no well-accepted reference ranges for testosterone concentrations in women. They hypothesized serum testosterone concentrations would exhibit an age-related decline in the subjects and show an increasing trend at mid-cycle, and SHBG concentrations would remain relatively stable across the age ranges studied. Previous researched cited reported that testosterone in serum is primarily bound to serum proteins, with a very small fraction circulating as a free fraction, and that “free testosterone” concentrations are even more challenging to reliably measure. Other research cited suggested that a number of reference ranges have been published for serum testosterone concentrations in premenopausal women, and that most of these available ranges are derived from a relatively small number of subjects (a number below the minimum of 125, as required by the National Committee for Clinical Laboratory Standards). Additionally, research cited emphasized women with low testosterone values do not necessarily have low libido, while many pre- and postmenopausal women with low libido do have low testosterone values.

Testosterone serum samples were collected from a total of 161 subjects used to generate the reference ranges. One hundred and twenty-one volunteers were employees of Quest Diagnostics Nichols Institute (San Juan Capistrano, CA, USA) and were predominately Asian-American and Caucasian. An additional 40 de-identified Caucasian and Hispanic subjects who participated in a prior study and whose clinical history and menstrual cycle were available were also used. All participants were self-proclaimed as healthy, premenopausal women between 18 and 49 years of age with regular menstrual cycles. Blood samples used for analysis were collected between 8am and 10am. Serum samples were analyzed for testosterone, SHBG, and LH using validated methods developed by Quest Diagnostics, Inc. Serum testosterone availability was log-transformed while square root transformation was used to measure and record SHBG data.

A weighted average of the values across phases was computed for each hormone in order to determine the average hormone exposure over the entire menstrual cycle. Weighted quantile regression with age as a covariate was used to estimate various percentiles of the hormone distributions. Results reported suggested that age was statistically significant for all testosterone analytes, indicating there was an association with age effect (decline of about 20% over the age-range). Age was not statistically significant for SHBG. The variations of hormones and SHBG across menstrual cycle were consistent with the author’s hypothesis.

The authors concluded reference ranges for bioavailable, total and free testosterone, and SHBG were established in premenopausal women using validated immunoassays (a procedure used for measuring or detecting specific proteins or other substances through their properties as antibodies or antigens) on a sufficient number of subjects consistent with recommendations by the National Committee for Clinical Laboratory Standards. As a point of interest, the percentiles reported for a 30-year-old woman were: testosterone, 15–46 ng/dL; free testosterone, 1.2–6.4 pg/mL; calculated free testosterone, 1.3–5.6 pg/mL; bioavailable testosterone, 1.12–7.62 ng/dL; and SHBG 18–86 nmol/L.

Tuomisto et al. (2012) investigated the association of serum oestradiol (sic) level, age, and education with cognitive performance in peri- and late postmenopausal women. The authors asserted that around and after menopause women often report increasing cognitive difficulties, especially problems with concentration and memory. Previous research by the authors included reports that neuropsychological cognitive measures associated with menopause suggested cognitive difficulties may be time-limited to perimenopause only, and relieve soon in postmenopause. Other research included evidence that higher endogenous oestradiol levels are connected with better cognitive performance in selected functions in older women, that oestrogen receptors are broadly distributed in the brain, and that oestrogen is involved in the regulation of neurotransmitters essential for cognitive functioning. The authors hypothesized it is possible, therefore, that endogenous oestrogen levels play a significant role in cognitive performance around the menopausal transition.

Previous research cited showed an age-related decline in working memory and cognitive processing speed, episodic memory, verbal attention, and verbal performance, as well as in cognitive plasticity. Additionally, numerous physiological and neuroanatomical and physiological changes occur in the brain, such as deterioration in neurotransmission and cortical atrophy. They also noted no significant loss of neurons seems to take place in the aging brain, rather a decline of brain white-matter volume might explain normal cognitive aging changes. Finally, prior research also claimed education has been linked to improving cognitive abilities like memory, attention, and executive functions.

Participants were enrolled through newspaper advertisements and 48 women were recruited; 21 were perimenopausal (43–51 years), and 27 were late postmenopausal (59–71 years). The criteria for exclusion included severe cardiovascular conditions, endocrinological disorders, neurological disorders, mental disease, sleep disorders (previously diagnosed and treated), abuse of medications or alcohol, use of antipsychotic or sleeping pills, or ongoing malignancies. Women using HT were accepted if at least 12 months had passed since the end of treatment. All women were non-smokers.

Prior to the study, a urine drug screen was given; leukocytes, thrombocytes, blood hemoglobin,, serum thyrotropin and free thyroxin were measured; and all women with abnormalities were excluded. In participants aged 43–51 years the PM state was established and confirmed by serum follicle stimulating hormone (FSH) ranges below 25 IU/l and ongoing menstrual cycle. PMO women were defined by FSH, amenorrhoea (official end of menstrual cycle), and age. Mean age for menopause was (m= 50.1).

BDI, Beck Depression Inventory; MMSE, Mini-Mental State Examination; EQ-5D, Euro Quality of Life-questionnaire; and VAS, Visual Analog Scale, were used to evaluate global cognitive functioning, symptoms of depression, cognitive impairment or depression, subjective quality of life, and state of health. Blood samples for serum oestradiol (sic) (E2: Spectria® RIA, Orion Diagnostica, Finland) and FSH (Delfia® TR-IFMA, Wallac, Finland) measures were obtained on the day of cognitive testing. Oestraidol ranges were also established.

Cognitive measurements evaluated visuomotor functions, visuoconstructive skills, verbal functions, visual and verbal episodic attention, and memory. All perimenopausal women were tested during the follicular phase of their menstrual cycle. Block design was used to measure visuomotor functions and skills. Episodic memory was measured using the modified version of the Rey auditory verbal learning test (RAVL). The Benton visual retention test ( form C) was used to test visual episodic memory. Attention was measured using the Paced Auditory Serial Addition Test. The CogniSpeed© software measures were used to observe and measure cognitive processing. The Bourdon–Wiersma-test measured visual attention. Shared attention was assessed by using a dual task.

The authors’ results showed that perimenopausal women performed better in the tests of visual episodic memory and visuomotor functions. Delayed and immediate recall showed PM women made fewer errors than PMO women. With regard to attention measures, PM women performed better in all but one CogniSpeed task on controlled cognitive processing and attention. No differences were reported in verbal episodic memory or verbal functions. Older age was associated with poorer performance in the test of verbal episodic memory in PM women.

The authors reported in PMO women, age was associated with reduced performance in attention, visuomotor functions, verbal and visual episodic memory, but not in verbal functions. The older the women, the poorer they scored in the Block Design, and older age was associated with fewer recalled words in RAVL testing. Regarding attention tests, older age was also shown to be connected with less correct responses, as well as with the Bourdon-Wiersma test.

Education was shown to explain performance in tests of attention and verbal episodic memory verbal and visuomotor functions, but not in visual episodic memory in PMO women. More education was associated with better performance and cognitive abilities on verbal tests, while attention tests showed the more education, the better the scores over all variables. In general, the authors asserted that cognitive performance was well-preserved into late postmenopause. PM women were shown to perform better than PMO women in tests of attention, visual episodic memory, and visuomotor functions. No differences in verbal functions and in verbal episodic memory were identified. The authors argued that the length of education seemed to explain most of the variation in cognitive performance in postmenopausal women, when evaluating effects of age and education. In PM women the age effect was observed mostly in verbal episodic memory.

In this study, the association between longer education and better test performance was found only in postmenopausal women. The authors discussed that education might offer a protection against cognitive decline observed even in healthy aging, and that education may compensate the age-related cognitive decline. Further, that higher education may protect against mild cognitive impairment and neurodegenerative diseases.

The authors also reported that the only association between E2 and cognitive performance was observed in visual episodic memory, and did not support their hypothesis that higher E2 level was related to poorer performance. They also noted that research illustrates both pro and con evidence regarding the idea that restoring hormone levels with HT after menopause improves cognitive performance in naturally menopausal women. The authors concluded that, in general, both exogenous and endogenous female sex hormones for cognition remains an ongoing query, yet claim the effect in menopausal transition is marginal. Tuomisto, et al., asserted their research provided a vital scientific implication: “…menopause, a natural event in women's life span, is not inevitably an epochal hallmark for cognitive decline, that cognitive performance is quite well preserved still in late postmenopause,” and that differences between PM and PMO women may be unrelated to hormonal factors. Finally, they suggested this study may have been biased due to the subject selection process; women recruited via newspapers may have led women with concerns about cognition or health to volunteer for the study. Lastly, they offer that they carefully screened for this, hoping to reduce the possibility of such a bias (2008).

The effects of testosterone on PM women have been explored, revealing memory problems, mood swings, vaginal dryness, problems sleeping, and hot flashes among the specific symptoms that have been generally associated with perimenopause (Gotmar et al., 2008). Making decisions about hormone replacement for perimenopausal women can be an overwhelming process. Deciphering one symptom from the next can be daunting, especially given that some of the symptoms associated with perimenopause, such as night sweats and loss of sex drive, may also be symptoms pointing to a variety of maladies like breast cancer or Parkinson’s disease (Theroux, 2010). We have been shown how lower testosterone concentrations are associated with lower quality of life but not lower sexual well-being in peri-menopausal women, suggesting there may be other elements involved that contribute to perimenopausal symptoms (Gotmar et al., 2008).

Additionally, researchers have argued there is mounting evidence, both pro and con, associated with HT. Whether choosing HT or bioidentical hormone replacement therapy, adding testosterone adds a whole other level of complication: “Androgen deficiency in women is increasingly recognized as a new clinical syndrome, and has raised our awareness of the importance of accurate and well-validated measurements of serum free testosterone (T) concentrations in women” (Miller et al., 2004). Research has confirmed that health care professionals currently have “…no well-accepted reference ranges for testosterone concentrations in women” (Braunstein et al., 2011). Furthermore, it was argued that there are insufficient data to assess the risk associated with long term HRT (particularly testosterone replacement) use in perimenopausal women or postmenopausal women who are younger than 50 years of age (Marjoribanks, , & 2012). Additionally, it was argued that menopause is a natural event in women's life and not an inevitable hallmark for cognitive decline, and that differences between PM and PMO women may be unrelated to hormonal factors (Tuomisto et al., 2012). Overall, experts agree that the use of HRT presents benefits and risks that have not changed in the last few years; the advice is to use the lowest dose for the shortest period of time. Further, women with PM should be encouraged to use HRT until the age of actual menopause (Holloway, 2010).

Suggestions for further research included more studies aimed at understanding the complexity of mechanisms and causes associated with perimenopausal symptoms and the effects of testosterone, including cognitive decline, sexual dysfunction, adrenal functions, genetic predispositions, and more general research on the PM population, including factors other than hormonal that may affect PM women.

It may also be interesting to note that up until the early 1960s what we call PM symptoms were frequently admonished as over-sensitivity, often referred to in medical terms as “hysteria” (a catch-all mental disorder for women with chronic “female complaints”). This so-called mental illness was treated with psychotherapy, tranquilizers, in many cases with institutionalization and, in some severe cases, with electric shock therapy or lobotomization. Ironically, some forty years later we have come to find that lack of emotion or absence of empathy can be linked with psychopathology: a psychological character disorder commonly associated with rapists, child molesters, and serial killers, largely represented in the male population.

Author Note: This paper was prepared for Psychology 3047, Hormones and Behavior, taught by Dr. Afshin Gharib.

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