220 Hormonal Changes in Menopause and Implications on Sexual Health Anneliese Schwenkhagen, MD Gynaekologicum Hamburg, Hamburg, Germany DOI: 10.1111/j.1743-6109.2007.00448.x ABSTRACT Introduction. The menopause is characterized by an array of changes to the female body caused by modulations which occur in the production of estrogens and androgens. The ovaries are important sites of testosterone production in the peri- and postmenopausal women, but the contribution of testosterone pro-hormones from the adrenal glands falls precipitously to the extent where the ovaries cannot correct the deficit. This results in a net decline in circulating testosterone levels. Aims. This paper gives an overview of this interesting subject area. Researchers have cogitated on the relationship between the physical effects of the menopause and the observed declines in testosterone levels, but it is now much clearer that falling testosterone levels cannot explain all of these changes. Main Outcome Measures. The cessation of follicular functioning results in a steep decline in the production of estrogens. This modulation is responsible for the physical manifestations of the menopause hot flushes, sleep disturbances, mood changes, bleeding problems, local urogenital problems, vaginal changes, etc. Methods. A review of the pertinent literature was conducted to investigate hormonal changes around the menopause. A précis of the salient information is presented here. Results. Although the most obvious and well-known effects of the menopause are due to the decline of estrogen levels, the effects of falling testosterone levels are subtle, but by no means less significant. Reductions in sexual motivation, sexual arousal, vaginal lubrication, etc. are all associated with plummeting androgen levels. Conclusions. Today, several options exist for the treatment of the endocrinological changes associated with the menopause. Estrogen deficiency can be corrected with hormone replacement therapy and topical preparations for the genitalia. A new transdermal system for the administration of testosterone shows a great deal of potential for the treatment of androgen deficiency. Schwenkhagen A. Hormonal changes in menopause and implications on sexual health.. Key Words. Menopause; Estrogen; Androgen; Testosterone; Deficiency Introduction The menopause is considerably more than just the cessation of ovarian function and modulation of sex hormone levels. A complete understanding of the complex phenomenon of the menopause hinges on the consideration of the various facets of the condition [1 3]. First, there are the physiological issues, which encompass all the important hormones, general health, and medication. The second facet is represented by psychological issues, which can embrace depression and a panoply of conditions. A considerate and loving partner, or the loss thereof, carries significant ramifications for the menopausal woman and can be assigned to partner issues. Finally, there are the sociocultural issues, including religion and anxieties regarding finances and the future. Obviously, these elements are not mutually exclusive from one another. The psychological, sociocultural, and partner issues are all intertwined, impinging directly on somatic elements, here represented by physiological issues. The Endocrinology of the Menopause From an endocrinological point of view, the menopause is characterized by significant changes. 2007 International Society for Sexual Medicine
Hormonal Changes and the Menopause 221 Table 1 Hormone levels in relationship to final menstrual period The Melbourne Women s Midlife Health Project [4] Years from final menstrual period T (nmol/l*) DHEAS (mmol/l*) FSH (IU/L*) P < 0.001 E 2 (pmol/l*) P < 0.001 Inhibin (IU/L*) P < 0.001-4 1.29 1.93 13.70 235.53 150.95-3 1.36 1.91 16.20 219.60 131.66-2 1.41 2.03 25.90 192.44 131.13-1 1.42 2.00 46.85 120.72 92.83 0 1.33 1.93 74.71 62.09 79.53 1 1.29 1.89 94.22 43.60 66.59 2 1.27 1.86 98.31 36.40 60.14 3 1.27 1.90 94.46 40.28 61.08 *Geometric mean. = no change; = increase; = decrease. DHEAS = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; T = testosterone. The longitudinal Australian study followed a cohort of women for 8 years, some of whom were menstruating for a considerable portion of the study period (Table 1) [4]. The results provide an interesting insight into the endocrinology of the menopause (Table 1). The findings show that as the follicles decline and as follicular functioning diminishes there is a concomitant decrease in the levels of estradiol and inhibin, conversely, there is an increase in the levels of follicular stimulating hormone. These changes are at their most marked in the last year before the menopause. Interestingly, androgen levels are remarkably consistent around the time of menopause. However, when our view is expanded to include the whole female life span we see that the age/androgen relationship is not that simple. Androgens Davison and coworkers measured testosterone levels in a reference population of 595 female patients, aged between 18 and 75 years, recruited from the community over a period of 15 months. This large data set shows that testosterone levels decline by around 55%, if you compare the youngest age group with the oldest (Figure 1) [5]. The level of dehydroepiandrosterone sulfate (DHEAS), the adrenal prohormone of testosterone, was also shown to decline markedly with age. Comparing the youngest age group with the oldest shows there is a precipitous 77% decline in the levels of this hormone [5]. To facilitate a complete understanding of the place of androgens in the menopause, it is necessary to assess what is known regarding the production/metabolism of these hormones and the role of the ovaries. In young women, the contribution of the adrenal glands to the DHEAS pool is approximately 90%, while peripheral conversion in the liver and small intestine is the source of the remainder [6,7]. With respect to testosterone in the premenopausal female, 50% of the circulatory levels of this hormone represent equal contributions from the ovaries and adrenal glands. With increasing age, the contribution of the adrenal glands, the peripheral tissue, and the ovaries to the DHEAS pool remains broadly the same; however, the contribution of the ovaries to the testosterone pool increases significantly, rising from 25% in the premenopausal woman to 50% in the postmenopausal woman (Figure 2) [6,7]. Therefore, the ovaries are obviously very important in the production of testosterone in peri- and postmenopausal women. This observation contradicts the general relationship between androgen levels and aging. How do testosterone levels decrease, if the ovary steps up its contribution in postmenopause? The answer to this lies above the kidneys. The production of the testosterone prohormones (dehydroepiandrosterone and DHEAS) by the adrenal glands decreases to the extent where the increased production by the ovaries cannot correct the deficit, resulting in a net decline in testosterone levels (Figure 2). Removing the ovaries would provide conclusive proof of this assumption. Theoretically, removing the ovaries should result in a decline in testosterone levels and this is indeed what can be seen. Laughlin et al. in 2000 measured total testosterone levels and bioavailable testosterone in women with intact uteri and ovaries, women who had a hysterectomy with ovarian conservation and women who had a hysterectomy and bilateral ovariectomy. The latter group showed low levels of total and bioavailable testosterone, compared with women whose ovaries were intact. All the women in this study were more than 50 years old, so therefore a significant difference in testosterone levels exists between naturally menopausal women and surgically menopausal women. This leads us to the hypothesis that the stromal cells of the ovaries and
222 Schwenkhagen Total testosterone (nmol/l) 3 2 1 0 18-24 25-34 35-44 45-54 55-64 65-75 Age group (years) n=595 Figure 1 Total testosterone levels decline with age [5]. not the follicles are important in androgen production (Figure 3) [9]. Dennerstein et al. have also shown that the menopausal transition adversely affects sexual functioning, with significant increases in responsivity, frequency of sexual activity and libido and significant increases in dyspareunia and partner problems [10]. What are the causes of these observations? Are the changing hormone levels the cause or is it the general phenomenon of the menopause? To answer these questions we must address another element of the menopausal hormone milieu. Estrogens What do we know about estrogens and the menopause? With the cessation of follicular functioning and the decline of follicles a menopausal women will exhibit a suite of symptoms, synonymous with this transition. These include hot flushes, sleep disturbances, mood changes, bleeding problems, local urogenital problems, thinning of the vaginal mucosal epithelium and atrophy of vaginal wall smooth muscle, vaginal dryness and increased vaginal ph, reduction in intraurethral pressure, bladder size, thickness of mucous membranes, reduction in pelvic muscle tone, and an increased sensitivity to pain [2,11]. Many of these symptoms can have a direct effect on sexual functioning. The Melbourne Women s Midlife Health Project revealed the relative effects of hormones and relationship factors on sexual function [4]. In this study the key predictors of sexual response included prior level of sexual function, change in partner status, feelings for partner and estradiol levels. The key predictors of dyspareunia were prior level of dyspareunia and estradiol levels. The predictors used to assess the frequency of sexual activities were prior level of sexual function, change in partner status, feelings for partner, and level of sexual response. Causes of Androgen Deficiency in Women The decline in androgens is a normal consequence of the aging process [12]. The levels of the androgens in the body can also fall as a result of ovarian insufficiency due to medical intervention, such as, oophorectomy, hysterectomy, premature menopause after chemo- or radiotherapy [12]. Declines in androgens arising from adrenal insufficiencies can be due to adrenal failure or surgery [12]. Low levels of the androgens can also be attributed to ACTH +ve -ve Cortisol Pituitary Estradiol LH +ve Adrenals 90% DHEA-S -ve 60% DHEA 60% 70% Androstendione 20% Ovaries Peripheral conversion Peripheral conversion 40% Testosterone DHT 50% Figure 2 Postmenopausal androgen metabolism [7,8]. ACTH = adrenocorticotropic hormone; DHEA = dehydroepiandrosterone; DHEAS = dehydroepiandrosterone sulfate; DHT = dihydrotestosterone; LH = luteinizing hormone.
Hormonal Changes and the Menopause 223 A B nmol/l nmol/l 0.6 0.4 0.2 0 0.15 0.1 0.05 0 Intact Ovarian conservation Bilateral oophorectomy a a a, b a, c Intact Ovarian conservation Bilateral oophorectomy Figure 3 Menopausal transition adversely affects sexual functioning [9]. (A) Total testosterone. (B) Bioavailable testosterone. a: P < 0.001 vs. intact. b: P < 0.001 vs. hysterectomy with ovarian conservation. c: P < 0.01 vs. hysterectomy with ovarian conservation. combined hypopituitarism and autoimmune mediated adrenal and ovarian failure [12]. Iatrogenic estrogen replacement therapy, antiandrogen therapy, oral contraception, and chronic glucocorticosteroid treatment can also result in declines in the levels of androgens [12]. As with estrogens, the decline in androgen levels can have significant effects on the body. Much of what we know about the effects of androgens in women is derived from the symptomatology of women in androgen-deficient states, i.e., women who have lost their ovaries due to surgery, chemotherapy, or radiation therapy. This complex of symptoms is now referred to as female androgen insufficiency [13,14]. Typically, the symptoms of androgen insufficiency include reductions in the following: sexual motivation, sexual fantasies, sexual enjoyment, sexual arousal, vaginal lubrication, vasocongestion, pubic hair, bone mass, muscle mass, and quality of life [13]. An element of female androgen insufficiency is hypoactive sexual desire disorder (HSDD) with its extremely important quality of life issues [15 17]. A study involving 2,467 women (aged 20 70 years) from France, Germany, Italy, and the United Kingdom with three clear objectives was undertaken to investigate HSDD [15]. First, the prevalence of the HSDD in women who have undergone hysterectomy and bilateral oophorectomy (surgical menopause) with that of premenopausal or naturally menopausal women was investigated. Second, the relationship between low sexual desire and sexual activity and behavior was also examined and last the relationship between low sexual desire and sexual or partner relationship satisfaction was assessed. To reach the objectives, the validated study instruments of PFSF (Profile of Female Sexual Function ), PDS (Personal Distress Scale ) and a sexual activities measure were employed. This study showed that a greater proportion of surgically menopausal women had low sexual desire compared with premenopausal or naturally menopausal women (odds ratio [OR] = 1.4; confidence interval [CI] = 1.1, 1.9, P = 0.02). Also, surgically menopausal women were more likely to have HSDD than premenopausal or naturally menopausal women (OR = 2.1; CI = 1.4, 3.4; P = 0.001). There was a high degree of correlation between sexual desire scores, sexual arousal, orgasm, and sexual pleasure (P 0.001). This demonstrated that low sexual desire is frequently associated with decreased functioning in other aspects of sexual response. Those women with low sexual desire were less likely to engage in sexual activity with a concomitant dissatisfaction with their sex life and partner relationship compared with women with normal desire (P 0.001). This study concluded that surgically menopausal women are at increased risk of developing HSDD and the diminished sexual and partner relationship this condition is associated with [15]. Most of the studies on testosterone treatment in women published to date have focused on the effects of testosterone on sexual functioning and psychological well-being. Since the mid-1980s, accumulating evidence has been published suggesting that adding testosterone to conventional hormonal therapy has a beneficial effect on sexual functioning in postmenopausal women. The randomized controlled trials shown in Table 2 demonstrate the efficacy of testosterone therapy in correcting sexual desire disorder in postmenopausal women [18,19]. However, most of the earlier studies employed testosterone preparations not specifically designed for women. For example, depot formulations such as pellets and injectable testosterone induce supraphysiological androgen levels for several weeks. Oral products containing methyltestosterone or testosterone undecanoate
224 Schwenkhagen Table 2 Randomized controlled trials of testosterone for sexual desire disorder in postmenopausal women [18] Year Author Intervention (dose/day) Menopause type N Duration (months) Design Result 1983 Dow Implants: E (50 mg) T (100 mg) I, N 40 4 SB, PG NS 1985 Sherwin Inj: T enan (200 mg); T enan (150 mg) + E dien I 53 3 DB, CO S (7.5 mg) + E benz (1 mg); E val (10 mg) 1987 Burger Implants: E (40 mg) T (100 mg) I, N 20 6 SB, PG S 1995 Davis Implants: E (50 mg) T (50 mg) I, N 34 24 SB, PG S 1998 Sarrel Oral: EE (1.25 mg) mt (2.5 mg) I, N 20 2 DB, PG S 2000 Shifren Oral: CEE (0.625 mg) T patch (150 or 300 mg) I 75 3 DB, CO S 2002 Floter Oral: E val (2 mg) T und (40 mg) I 50 6 DB, CO S 2003 Lobo Oral: EE (0.625 mg) mt (1.25 mg) I, N 218 4 DB, PG S 2005 Braunstein Oral estrogen T patch (150, 300, or 450 mg/day) I 447 6 DB, PG S 2005 Simon T patch (300 mg/day) I 562 6 DB, PG S 2005 Buster Oral/transdermal estrogen T patch (300 mg/day) I 533 6 DB, PG S 2006 Shifren T patch (300 mg/day) N 549 6 DB, PG S 2006 Davis Transdermal estrogen (50 mg/day) I 77 4 DB, PG S CEE = conjugated equine estrogens; CO = crossover; DB = double blind; E = estradiol; E benz = estradiol benzoate; E dien = estradiol dienanthate; EE = esterified estrogens; E val = estradiol valerate; I = surgically induced menopause; Inj = injection; mt = methyltestosterone; N = natural (spontaneous) menopause; NS = nonsignificant results; PG = parallel-group; S = significant results; SB = single blind; T = testosterone; T enan = testosterone enanthate; T und = testosterone undecanoate. have short half-lives and demonstrate an unfavorable pharmacokinetic profile with supraphysiological androgen levels after administration followed by a rapid decline. These oversights in product administration are significant pitfalls in the earlier studies, but the newer studies have addressed this problem by utilizing a transdermal delivery system. This system delivers a natural testosterone through the skin that has a more favorable pharmacokinetic profile and is specifically designed for use in women. The Investigation of Natural Testosterone In Menopausal women Also Taking Estrogen (Surgically Menopausal) (INTI- MATE SM) 1 and 2 studies are a good example of these recent studies where natural testosterone was administered transdermally. SM 1 and SM 2 involved 562 and 532 women, respectively, enrolled in the United States, Canada, and Australia [6,20]. In INTIMATE SM 1, the mean increase from baseline in total satisfying sexual activity was 2.10 satisfying episodes/ 4 weeks in testosterone-treated women, compared with 0.98 satisfying episodes/4 weeks in the placebo group; the mean treatment difference was 1.11 (95% CI 0.5 1.73, P = 0.0003). The corresponding figures in INTIMATE SM 2 were 1.56 and 0.73 satisfying episodes/4 weeks, respectively (P = 0.001). Thus transdermal testosterone was associated with a 74% and 51% increase, compared with baseline, in total satisfying sexual activity in INTIMATE SM 1 and SM 2, respectively. In both studies, significant increases in total satisfying sexual activity were observed after 5 weeks of treatment, with maximal and consistent effects being achieved from week 12. In both studies, testosterone treatment was also associated with significant increases in the frequency of total sexual episodes and orgasms, compared with placebo. The studies also demonstrated significant improvements in other measures, assessed using the validated study instruments, PFSF and PDS. The instrument showed significant improvements in all domains of sexual function in testosterone-treated women, compared with the control group. In INTIMATE SM 2, the mean increase in sexual desire score at week 24 in testosterone-treated women was 10.57 (indicating a 49% increase from baseline), compared with 4.29 in placebo-treated women (P < 0.001); similarly, in INTIMATE SM 1, sexual desire scores increased significantly, compared with placebo at 4 weeks and at all other time points except for week 8 [6,20]. In many of the assessed domains the improvement in the treatment group from baseline was almost double that of the placebo group. Both studies also showed a significant decrease in personal distress in testosterone-treated women, compared with the placebo group. In testosteronetreated women, personal distress scores decreased by an average of 65% in INTIMATE SM 1 and 68% in INTIMATE SM 2, compared with 40% and 48%, respectively, in the corresponding placebo groups. As the majority of women reach menopause naturally it is particularly important how transdermal testosterone can be used to treat these patients. To this end Shifren and coworkers assessed the efficacy and safety of the transdermal testosterone patch in naturally menopausal women on concomitant oral estrogen or estrogen/
Hormonal Changes and the Menopause 225 progestin (if uterus present) [21]. This study showed that the primary efficacy measure of total satisfying sexual episodes increased significantly from baseline in those women receiving transdermal testosterone compared with the placebo group (2.1 0.28 vs. 0.5 0.23 satisfying episodes per 4 weeks [P < 0.0001]) [21]. The testosterone cohort also exhibited statistically significant improvements in sexual desire and personal distress (secondary efficacy measures) compared with women receiving the placebo [21]. Conclusions A wealth of literature exists on the changes that occur in hormone levels around the menopause transition and, more broadly, over the entire life span. Modulation of the concentration of androgens and estradiols in the blood, post menopause, has been shown to be associated with declines in the central aspects of sexual functioning, including libido and subjective arousal, possibly via indirect mechanisms. For example, does a loss of estradiol lead to the manifestation of depression and a consequent negative effect on sexual functioning? Although it is possible to infer putative relationships between changing hormone levels and sexual functioning, we should be mindful that this is but one small part of a complex web of factors influencing sexual functioning alone or in concert. Several recent studies have shown that some of the symptoms of the menopause arising as a result of endocrinological changes can be ameliorated with hormone therapy. The loss of sexual desire in surgically and naturally menopausal women is an important quality of life issue that can impinge not only on personal well-being but also on partner relationships. Addressing the deficit in testosterone level that causes a loss of sexual desire is now possible via transdermal delivery of testosterone offering hope to the many women with HSDD. Although the menopause is a complex condition, a number of therapeutic options now exist for the management of the disconcerting symptoms [22,23]. Estrogens in various guises can be administered to alleviate the systemic symptoms of hot flushes and the localized symptoms of genital atrophy. Androgen deficiency has, historically, been far more difficult to treat, but a new system for the transdermal delivery of testosterone provides a great deal of potential for alleviating HSDD, which is possibly one of the most emotive symptoms of the menopause. This treatment offers hope to countless women who feel their sexual longings have been prematurely lost due to the ravages of the menopause. Acknowledgments The author would like to thank Ross Piper for editorial support in the preparation of this manuscript. Corresponding Author: Anneliese Schwenkhagen, MD, Altonaerstr 59, D 20357 Hamburg, Germany. Tel: +49 40 306 8360; Fax: +49 40 306 83669; E-mail: schwenkhagen@hormone-hamburg.de Conflict of Interest: Dr. Schwenkhagen has consulted with Procter & Gamble Pharmaceuticals. References 1 Dennerstein L, Hayes RD. Confronting the challenges: Epidemiological study of female sexual dysfunction and the menopause. J Sex Med 2005;2(suppl 3):118 32. 2 Graziottin A, Leiblum SR. Biological and psychosocial pathophysiology of female sexual dysfunction during the menopausal transition. J Sex Med 2005;2(suppl 3):133 45. 3 Jeong GW, Park K, Youn G, Kang HK, Kim HJ, Seo JJ, Ryu SB. Assessment of cerebrocortical regions associated with sexual arousal in premenopausal and menopausal women by using BOLDbased functional MRI. J Sex Med 2005;2:645 51. 4 Dennerstein L, Lehert P, Burger H. The relative effects of hormones and relationship factors on sexual function of women through the natural menopausal transition. Fertil Steril 2005;84:174 80. 5 Davison SL, Bell R, Donath S, Montalto JG, Davis SR. Androgen levels in adult females: Changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 2005;90:3847 53. 6 Buster JE, Kingsberg SA, Aguirre O, Brown C, Breaux JG, Buch A, Rodenberg CA, Wekselman K, Casson P. Testosterone patch for low sexual desire in surgically menopausal women: A randomized trial. Obstet Gynecol 2005;105(5 Part 1):944 52. 7 Lobo RA. Treatment of the postmenopausal women: Basic and clinical aspects. 2nd edition. Philadelphia, PA: Lippincott Williams & Wilkins; 1999. 8 Simon JA. Estrogen replacement therapy: Effects on the endogenous androgen milieu. Fertil Steril 2002;77(suppl 4):S77 82. 9 Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, von Muhlen D. Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: The Rancho Bernardo Study. J Clin Endocrinol Metab 2000;85:645 51. 10 Dennerstein L, Dudley E, Burger H. Are changes in sexual functioning during midlife due to aging or menopause? Fertil Steril 2001;76:456 60.
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