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Hormonal changes during menopause
Maturitas 63 (2009) 135–137
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
Hormonal changes during menopause Farook Al-Azzawi a,∗ , Santiago Palacios b a b
Gynaecology Research Unit, University Hospitals of Leicester, Victoria Building, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom Palacios Institute of Woman’s Health, Madrid, Spain
a r t i c l e
i n f o
Article history: Received 27 January 2009 Received in revised form 9 March 2009 Accepted 11 March 2009 Keywords: Androgens Estrogens Menopause Sex hormones
a b s t r a c t Ovarian senescence occurs gradually during the fourth and fifth decades of life, leading to menopause at an average age of about 51 years. This senescence results in a changing hormonal milieu, with decreases in the levels of estrogens and androgens. Similar changes may be induced by surgical menopause (bilateral oophorectomy) or ovarian failure resulting from cancer treatment. The declining levels of estrogens and androgens affect many tissues of the body and can produce a variety of signs and symptoms, including vasomotor symptoms, decreased bone density, changes in mood and energy, loss of pubic hair and changes in the genital tissues, and effects on sexual function. Accurate measurement of testosterone levels in postmenopausal women requires methods that are validated in the lower ranges of testosterone level observed in this population. © 2009 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
3. 4. 5. 6.
The menopause transition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hormonal milieu during the menopausal transition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Oestrogen deficiency: pathophysiology and symptomatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Androgen deficiency: pathophysiology and symptomatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Androgen deficiency in women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Measurement of androgens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. The menopause transition Ovarian senescence is a gradual process that begins at around 35 years of age and reaches its culmination at the menopause at about 51 years of age. This decreasing in function is evidenced by a progressive decline in fecundity and increases in spontaneous miscarriages and menstrual irregularities in the second half of the 4th decade of life and the years that follow. The consequences of ovarian ageing and the resulting oestrogen deprivation have many phenotypic effects on tissue regeneration and maintenance. Collagen homeostasis in skin, bone and supportive ligaments of the generative tract is generally affected.
∗ Corresponding author. Tel.: +44 0116 2587506; fax: +44 0116 2586098. E-mail address: [email protected] (F. Al-Azzawi). 0378-5122/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2009.03.009
135 136 136 136 136 136 137 137 137 137 137
Epithelial thinness of the vagina and bladder trigone result in dyspareunia associated with vaginal dryness and urinary urgency and frequency, respectively. Neural plasticity and neuronal transmission are other vulnerable targets of oestrogen deficiency and may result in irritability, depressive moods, insomnia, poor concentration and declining memory. The earlier the age at which menopause occurs, the more profound its effects on the incidence of cognitive impairment and indeed on the incidence of coronary heart disease. Oestrogen induces nitric oxide synthase and improves lipoprotein metabolism, which are fundamental mechanisms in promoting a healthy arterial tree. The menopause and its management have attracted a great deal of interest in the last century for a number of reasons. Life expectancy in the western world has progressively increased from about 56 years at the turn of the 20th century, not far beyond the menopause, to around 80 years at present. As a result of this
136
F. Al-Azzawi, S. Palacios / Maturitas 63 (2009) 135–137
increase in life expectancy, one third or more of a woman’s life span is now spent postmenopause. In addition to the increasing number of women who are being exposed to long term oestrogen deficiency, definitions for quality of life and general wellbeing have been underlined by high expectations. The present perimenopausal population adopts the anti-ageing culture and turns away from strictly biologistic, negative, and ageist ideas. Finally, the diagnosis of the menopause is easy and its management with individualised hormonal replacement is highly effective. 2. Hormonal milieu during the menopausal transition 2.1. Oestrogen deficiency: pathophysiology and symptomatology The gradual decline in ovarian oestrogen production in the years prior to the complete cessation of menstruation (the menopause) is largely related to the number of remaining primordial follicles, the number of recruitable follicles in each ovarian cycle, and the proportion of these follicles that reach adequate maturity prior to ovulation. These ovarian changes may also lead to anovulation, which is frequently observed during this period. Therefore, a defective follicular phase may result in fewer granulosa cells being generated and less effective synthesis of oestradiol per growing follicle, less inhibin production, and then reduced negative feed back on FSH release—hence the gradual increase in FSH from mid 4th decade of life onwards. As a result, more follicles are recruited into a particular cycle which sometimes could collectively produce even higher serum oestradiol levels in the years leading to the menopause that may be adequate to stimulate the endometrium. Nonetheless, many women will experience vasomotor symptoms, irritability and insomnia while still menstruating. Further, a shorter and defective follicular phase contributes to the commonly observed frequent and sometimes heavy menstrual cycles in the years approaching the menopause. This phase of reproductive senescence is also called the climacteric and may last for about 4 years leading to the menopause. At the menopause, the final menstrual cycle, a dramatic decline in plasma oestradiol level occurs and the postmenopausal ovary will cease to contribute to oestradiol levels in blood. Instead, peripheral conversion of androstenedione into oestrone becomes prominent. Only 5% of thus formed oestrone is converted to oestradiol through the action of 17 hydroxysteroid dehydrogenase [1]. The activity of this enzyme is in a reversible reaction converting oestrone to oestradiol and back, dependening on the oxido-reductive state that prevails in the cell. Further, the amount of oestrone generated and the associated conversion to oestradiol continue to decline during the first year after menopause and stabilises thereafter. The amount of oestrone generated is a function of the abundance of androstenedione and age. The corpus luteum synthesises progesterone and in the absence of ovulation only basal levels derived from the adrenal glands are detected. In postmenopausal women, administration of ACTH dramatically increases while human chorionic gonadotrophin has no effect on progesterone levels, attesting to the negligible role of postmenopausal ovaries in progesterone production [2]. 2.2. Androgen deficiency: pathophysiology and symptomatology Dehydroepiandrosterone (DHEA) is produced in both the ovaries and the adrenal glands under the influence of luteinising hormone (LH) and adrenocorticotrophic hormone (ACTH), respectively. DHEA sulphate (DHEAS) is exclusively produced by the adrenal glands and is converted to DHEA by steroid sulphatase. Their declining plasma levels are due to age-related reduced steroid synthesizing capacity of the zona reticularis and due to ovarian ageing [3].
During the reproductive years, both the adrenal glands and the ovaries share equally in androstenedione production [4]. Bilateral oophorectomy in premenopausal women results in a 50% reduction in serum androstenedione levels while postmenopausal ovaries contribute only 20% of its total circulating levels. Since the metabolic clearance of androstenedione is not affected by ovarian function or age, the 30% drop represents the effect of ovarian senescence [5]. In premenopausal women, 50% of circulating testosterone is derived from peripheral conversion of androstenedione [1,6], while the remaining testosterone production is shared between the ovaries and the adrenal glands. In postmenopausal women, testosterone levels decrease compared to young women although ovarian synthesis after the menopause appears to contribute a higher proportion of circulating testosterone. This may be due to higher LH levels and their effect on ovarian stromal steroidogenesis. In a recent cross-sectional study, a different aspect of ovarian ageing was reported. The circulating levels of DHEA, androstenedione, and total and free testosterone were found to be highest during the third decade of life and to decline afterward in the remaining reproductive years. Around the age of 50, free and total testosterone levels decrease by about 50% [3]. Testosterone exists in circulation as free testosterone (1–2% of the total), loosely bound to albumin (31%) and tightly bound to sex hormone binding globulin (SHBG) (66%). It is the free and albumin-bound testosterone that is available to cells. Many clinicians and clinical investigators use the ratio of total testosterone to SHBG to derive the free testosterone index. Sex hormone binding globulin (SHBG) is a protein synthesised in the liver. Oestrogen stimulates its synthesis while all androgens suppress its hepatic synthesis. Obesity, particularly with upper abdominal distribution, also suppresses SHBG levels. In the postmenopausal period, SHBG levels decline and that may account for higher bioavailability of testosterone [7,8]. A decrease in bioavailable testosterone level may result from impaired testosterone production or from increased SHBG levels in the presence of normal testosterone production. It is therefore necessary to consider SHBG levels in the assessment of bioavailable testosterone in women. 3. Surgical menopause As can be expected, the removal of both ovaries in a premenopausal woman results in an abrupt decline in oestrogen to undetectable levels, a 50% reduction in androstenedione, and about 70% drop in DHEA and testosterone levels [9]. These women experience a sudden onset of the menopausal transition. In at least 30–50% of cases, symptoms of androgen deficiency are experienced despite “adequate” oestrogen replacement [10,11]. 4. Androgen deficiency in women Androgen deficiency may develop as a result of low androgen synthesis or low bioavailability due to elevated SHBG level. The main causes of low androgen production are those of ovarian failure, including natural and surgical menopause, menopause induced by cancer treatment, and premature ovarian failure. Other causes include impaired adrenal gland function (hypocorticism), hypopituitarism, and anorexia nervosa. A set of symptoms has been attributed to androgen deficiency in women but there is no general agreement as to whether they are part of the progression to natural menopause. Data on prevalence of these symptoms are derived from surveys into sexual dysfunction or from clinical studies on sexual dysfunction in women. Decline in testosterone levels may cause diminished sense of well-being, depression, decreased energy, decreased muscle mass
F. Al-Azzawi, S. Palacios / Maturitas 63 (2009) 135–137
and strength, decreased sexual desire, sexual receptivity, sexual arousal and orgasm, loss of pubic hair, changes in cognition and memory and declining testosterone levels may augment the risk of osteoporosis. 5. Measurement of androgens One of the main hurdles in the general acceptance of androgen deficiency as a condition is the lack of widely available, sensitive assays for testosterone in the lower ranges observed in women. Free testosterone concentration, as measured by equilibrium dialysis, is considered as the optimal assay but it is time-consuming and expensive. Total testosterone concentration is usually measured by radioimmunoassay, as it is a reflection of overall androgen production. Together with measurement of SHBG, it will enable the derivation of free testosterone index, which correlates well with the free or bioavailable testosterone levels. Other assay methods have been developed and as with the radio-immunoassay, all suffer shortcomings that largely focussed on standardisation and derivation of normative values in the lower range of the assay method used. The Endocrine Society had commissioned a group of experts who published their finding in 2007 [12]. DHEAS assays are readily available and are useful in assessing adrenal androgen production. Similarly, measurements of DHEA and androstenedione are available and robust enough for detailed assessment of androgens profile. 6. Summary The menopausal transition is a function of progressive decline in ovarian follicular population and reduced steroidogenetic capacity of ovarian stroma, as such it represents ovarian senescence. After the final menstrual cycle, oestrogen levels drop markedly and frequently are below the detection limits of the assay. Androgens production has been shown to decline with age from peak levels in the third decade of life down to 50% their values around the menopause. Surgical menopause is characterised by dramatically reduced levels of gonadal steroids and as many as 50% of women will present with androgen deficiency symptoms following surgery. Definitions of the androgen deficiency state have been hampered by reduced sensitivity of testosterone assays at the lower ranges. For most practical and investigative purposes, the free testosterone index is a valuable tool to help assessment of patients.
137
Conflict of interest F. Al-Azzawi and Santiago Palacios have been symposium speakers and advisory board members for several companies: Bayer-Schering, Novo Nordisk, Servier, Wyeth). They also receive research grants and consulting fees from the folowing companies: Wyeth, Servier and P&G. Acknowledgement The authors would like to thank Procter & Gamble Pharmaceuticals for their sponsorship of this work and the activities of the Group of European Experts on Female Sexual Dysfunction. References [1] Luu-The V, Dufort I, Pelletier G, Labrie F. Type 5 17beta-hydroxysteroid dehydrogenase: its role in the formation of androgens in women. Mol Cell Endocrinol 2001;171:77–82. [2] Vermeulen A, Verdonck L. Sex hormone concentrations in post-menopausal women. Clin Endocrinol (Oxf) 1978;9:59–66. [3] 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. [4] Longcope C, Franz C, Morello C, Baker R, Johnston Jr CC. Steroid and gonadotropin levels in women during the peri-menopausal years. Maturitas 1986;8: 189–96. [5] Grodin JM, Siiteri PK, MacDonald PC. Source of estrogen production in postmenopausal women. J Clin Endocrinol Metab 1973;36:207–14. [6] Horton R, Tait JF. Androstenedione production and interconversion rates measured in peripheral blood and studies on the possible site of its conversion to testosterone. J Clin Invest 1966;45:301–13. [7] Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL. A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab 2000;85:2832–8. [8] Gambera A, Scagliola P, Falsetti L, Sartori E, Bianchi U. Androgens, insulin-like growth factor-I (IGF-I), and carrier proteins (SHBG, IGFBP-3) in postmenopause. Menopause 2004;11:159–66. [9] Lobo RA. Androgens in postmenopausal women: production, possible role, and replacement options. Obstet Gynecol Surv 2001;56:361–76. [10] Nathorst-Boos J, von Schoultz B, Carlstrom K. Elective ovarian removal and estrogen replacement therapy—effects on sexual life, psychological well-being and androgen status. J Psychosom Obstet Gynaecol 1993;14:283–93. [11] Zussman L, Zussman S, Sunley R, Bjornson E. Sexual response after hysterectomy-oophorectomy: recent studies and reconsideration of psychogenesis. Am J Obstet Gynecol 1981;140:725–9. [12] Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society Position Statement. J Clin Endocrinol Metab 2007;92:405–13.
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
Hormonal changes during menopause Farook Al-Azzawi a,∗ , Santiago Palacios b a b
Gynaecology Research Unit, University Hospitals of Leicester, Victoria Building, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom Palacios Institute of Woman’s Health, Madrid, Spain
a r t i c l e
i n f o
Article history: Received 27 January 2009 Received in revised form 9 March 2009 Accepted 11 March 2009 Keywords: Androgens Estrogens Menopause Sex hormones
a b s t r a c t Ovarian senescence occurs gradually during the fourth and fifth decades of life, leading to menopause at an average age of about 51 years. This senescence results in a changing hormonal milieu, with decreases in the levels of estrogens and androgens. Similar changes may be induced by surgical menopause (bilateral oophorectomy) or ovarian failure resulting from cancer treatment. The declining levels of estrogens and androgens affect many tissues of the body and can produce a variety of signs and symptoms, including vasomotor symptoms, decreased bone density, changes in mood and energy, loss of pubic hair and changes in the genital tissues, and effects on sexual function. Accurate measurement of testosterone levels in postmenopausal women requires methods that are validated in the lower ranges of testosterone level observed in this population. © 2009 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
3. 4. 5. 6.
The menopause transition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hormonal milieu during the menopausal transition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Oestrogen deficiency: pathophysiology and symptomatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Androgen deficiency: pathophysiology and symptomatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgical menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Androgen deficiency in women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Measurement of androgens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. The menopause transition Ovarian senescence is a gradual process that begins at around 35 years of age and reaches its culmination at the menopause at about 51 years of age. This decreasing in function is evidenced by a progressive decline in fecundity and increases in spontaneous miscarriages and menstrual irregularities in the second half of the 4th decade of life and the years that follow. The consequences of ovarian ageing and the resulting oestrogen deprivation have many phenotypic effects on tissue regeneration and maintenance. Collagen homeostasis in skin, bone and supportive ligaments of the generative tract is generally affected.
∗ Corresponding author. Tel.: +44 0116 2587506; fax: +44 0116 2586098. E-mail address: [email protected] (F. Al-Azzawi). 0378-5122/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2009.03.009
135 136 136 136 136 136 137 137 137 137 137
Epithelial thinness of the vagina and bladder trigone result in dyspareunia associated with vaginal dryness and urinary urgency and frequency, respectively. Neural plasticity and neuronal transmission are other vulnerable targets of oestrogen deficiency and may result in irritability, depressive moods, insomnia, poor concentration and declining memory. The earlier the age at which menopause occurs, the more profound its effects on the incidence of cognitive impairment and indeed on the incidence of coronary heart disease. Oestrogen induces nitric oxide synthase and improves lipoprotein metabolism, which are fundamental mechanisms in promoting a healthy arterial tree. The menopause and its management have attracted a great deal of interest in the last century for a number of reasons. Life expectancy in the western world has progressively increased from about 56 years at the turn of the 20th century, not far beyond the menopause, to around 80 years at present. As a result of this
136
F. Al-Azzawi, S. Palacios / Maturitas 63 (2009) 135–137
increase in life expectancy, one third or more of a woman’s life span is now spent postmenopause. In addition to the increasing number of women who are being exposed to long term oestrogen deficiency, definitions for quality of life and general wellbeing have been underlined by high expectations. The present perimenopausal population adopts the anti-ageing culture and turns away from strictly biologistic, negative, and ageist ideas. Finally, the diagnosis of the menopause is easy and its management with individualised hormonal replacement is highly effective. 2. Hormonal milieu during the menopausal transition 2.1. Oestrogen deficiency: pathophysiology and symptomatology The gradual decline in ovarian oestrogen production in the years prior to the complete cessation of menstruation (the menopause) is largely related to the number of remaining primordial follicles, the number of recruitable follicles in each ovarian cycle, and the proportion of these follicles that reach adequate maturity prior to ovulation. These ovarian changes may also lead to anovulation, which is frequently observed during this period. Therefore, a defective follicular phase may result in fewer granulosa cells being generated and less effective synthesis of oestradiol per growing follicle, less inhibin production, and then reduced negative feed back on FSH release—hence the gradual increase in FSH from mid 4th decade of life onwards. As a result, more follicles are recruited into a particular cycle which sometimes could collectively produce even higher serum oestradiol levels in the years leading to the menopause that may be adequate to stimulate the endometrium. Nonetheless, many women will experience vasomotor symptoms, irritability and insomnia while still menstruating. Further, a shorter and defective follicular phase contributes to the commonly observed frequent and sometimes heavy menstrual cycles in the years approaching the menopause. This phase of reproductive senescence is also called the climacteric and may last for about 4 years leading to the menopause. At the menopause, the final menstrual cycle, a dramatic decline in plasma oestradiol level occurs and the postmenopausal ovary will cease to contribute to oestradiol levels in blood. Instead, peripheral conversion of androstenedione into oestrone becomes prominent. Only 5% of thus formed oestrone is converted to oestradiol through the action of 17 hydroxysteroid dehydrogenase [1]. The activity of this enzyme is in a reversible reaction converting oestrone to oestradiol and back, dependening on the oxido-reductive state that prevails in the cell. Further, the amount of oestrone generated and the associated conversion to oestradiol continue to decline during the first year after menopause and stabilises thereafter. The amount of oestrone generated is a function of the abundance of androstenedione and age. The corpus luteum synthesises progesterone and in the absence of ovulation only basal levels derived from the adrenal glands are detected. In postmenopausal women, administration of ACTH dramatically increases while human chorionic gonadotrophin has no effect on progesterone levels, attesting to the negligible role of postmenopausal ovaries in progesterone production [2]. 2.2. Androgen deficiency: pathophysiology and symptomatology Dehydroepiandrosterone (DHEA) is produced in both the ovaries and the adrenal glands under the influence of luteinising hormone (LH) and adrenocorticotrophic hormone (ACTH), respectively. DHEA sulphate (DHEAS) is exclusively produced by the adrenal glands and is converted to DHEA by steroid sulphatase. Their declining plasma levels are due to age-related reduced steroid synthesizing capacity of the zona reticularis and due to ovarian ageing [3].
During the reproductive years, both the adrenal glands and the ovaries share equally in androstenedione production [4]. Bilateral oophorectomy in premenopausal women results in a 50% reduction in serum androstenedione levels while postmenopausal ovaries contribute only 20% of its total circulating levels. Since the metabolic clearance of androstenedione is not affected by ovarian function or age, the 30% drop represents the effect of ovarian senescence [5]. In premenopausal women, 50% of circulating testosterone is derived from peripheral conversion of androstenedione [1,6], while the remaining testosterone production is shared between the ovaries and the adrenal glands. In postmenopausal women, testosterone levels decrease compared to young women although ovarian synthesis after the menopause appears to contribute a higher proportion of circulating testosterone. This may be due to higher LH levels and their effect on ovarian stromal steroidogenesis. In a recent cross-sectional study, a different aspect of ovarian ageing was reported. The circulating levels of DHEA, androstenedione, and total and free testosterone were found to be highest during the third decade of life and to decline afterward in the remaining reproductive years. Around the age of 50, free and total testosterone levels decrease by about 50% [3]. Testosterone exists in circulation as free testosterone (1–2% of the total), loosely bound to albumin (31%) and tightly bound to sex hormone binding globulin (SHBG) (66%). It is the free and albumin-bound testosterone that is available to cells. Many clinicians and clinical investigators use the ratio of total testosterone to SHBG to derive the free testosterone index. Sex hormone binding globulin (SHBG) is a protein synthesised in the liver. Oestrogen stimulates its synthesis while all androgens suppress its hepatic synthesis. Obesity, particularly with upper abdominal distribution, also suppresses SHBG levels. In the postmenopausal period, SHBG levels decline and that may account for higher bioavailability of testosterone [7,8]. A decrease in bioavailable testosterone level may result from impaired testosterone production or from increased SHBG levels in the presence of normal testosterone production. It is therefore necessary to consider SHBG levels in the assessment of bioavailable testosterone in women. 3. Surgical menopause As can be expected, the removal of both ovaries in a premenopausal woman results in an abrupt decline in oestrogen to undetectable levels, a 50% reduction in androstenedione, and about 70% drop in DHEA and testosterone levels [9]. These women experience a sudden onset of the menopausal transition. In at least 30–50% of cases, symptoms of androgen deficiency are experienced despite “adequate” oestrogen replacement [10,11]. 4. Androgen deficiency in women Androgen deficiency may develop as a result of low androgen synthesis or low bioavailability due to elevated SHBG level. The main causes of low androgen production are those of ovarian failure, including natural and surgical menopause, menopause induced by cancer treatment, and premature ovarian failure. Other causes include impaired adrenal gland function (hypocorticism), hypopituitarism, and anorexia nervosa. A set of symptoms has been attributed to androgen deficiency in women but there is no general agreement as to whether they are part of the progression to natural menopause. Data on prevalence of these symptoms are derived from surveys into sexual dysfunction or from clinical studies on sexual dysfunction in women. Decline in testosterone levels may cause diminished sense of well-being, depression, decreased energy, decreased muscle mass
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and strength, decreased sexual desire, sexual receptivity, sexual arousal and orgasm, loss of pubic hair, changes in cognition and memory and declining testosterone levels may augment the risk of osteoporosis. 5. Measurement of androgens One of the main hurdles in the general acceptance of androgen deficiency as a condition is the lack of widely available, sensitive assays for testosterone in the lower ranges observed in women. Free testosterone concentration, as measured by equilibrium dialysis, is considered as the optimal assay but it is time-consuming and expensive. Total testosterone concentration is usually measured by radioimmunoassay, as it is a reflection of overall androgen production. Together with measurement of SHBG, it will enable the derivation of free testosterone index, which correlates well with the free or bioavailable testosterone levels. Other assay methods have been developed and as with the radio-immunoassay, all suffer shortcomings that largely focussed on standardisation and derivation of normative values in the lower range of the assay method used. The Endocrine Society had commissioned a group of experts who published their finding in 2007 [12]. DHEAS assays are readily available and are useful in assessing adrenal androgen production. Similarly, measurements of DHEA and androstenedione are available and robust enough for detailed assessment of androgens profile. 6. Summary The menopausal transition is a function of progressive decline in ovarian follicular population and reduced steroidogenetic capacity of ovarian stroma, as such it represents ovarian senescence. After the final menstrual cycle, oestrogen levels drop markedly and frequently are below the detection limits of the assay. Androgens production has been shown to decline with age from peak levels in the third decade of life down to 50% their values around the menopause. Surgical menopause is characterised by dramatically reduced levels of gonadal steroids and as many as 50% of women will present with androgen deficiency symptoms following surgery. Definitions of the androgen deficiency state have been hampered by reduced sensitivity of testosterone assays at the lower ranges. For most practical and investigative purposes, the free testosterone index is a valuable tool to help assessment of patients.
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Conflict of interest F. Al-Azzawi and Santiago Palacios have been symposium speakers and advisory board members for several companies: Bayer-Schering, Novo Nordisk, Servier, Wyeth). They also receive research grants and consulting fees from the folowing companies: Wyeth, Servier and P&G. Acknowledgement The authors would like to thank Procter & Gamble Pharmaceuticals for their sponsorship of this work and the activities of the Group of European Experts on Female Sexual Dysfunction. References [1] Luu-The V, Dufort I, Pelletier G, Labrie F. Type 5 17beta-hydroxysteroid dehydrogenase: its role in the formation of androgens in women. Mol Cell Endocrinol 2001;171:77–82. [2] Vermeulen A, Verdonck L. Sex hormone concentrations in post-menopausal women. Clin Endocrinol (Oxf) 1978;9:59–66. [3] 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. [4] Longcope C, Franz C, Morello C, Baker R, Johnston Jr CC. Steroid and gonadotropin levels in women during the peri-menopausal years. Maturitas 1986;8: 189–96. [5] Grodin JM, Siiteri PK, MacDonald PC. Source of estrogen production in postmenopausal women. J Clin Endocrinol Metab 1973;36:207–14. [6] Horton R, Tait JF. Androstenedione production and interconversion rates measured in peripheral blood and studies on the possible site of its conversion to testosterone. J Clin Invest 1966;45:301–13. [7] Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL. A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab 2000;85:2832–8. [8] Gambera A, Scagliola P, Falsetti L, Sartori E, Bianchi U. Androgens, insulin-like growth factor-I (IGF-I), and carrier proteins (SHBG, IGFBP-3) in postmenopause. Menopause 2004;11:159–66. [9] Lobo RA. Androgens in postmenopausal women: production, possible role, and replacement options. Obstet Gynecol Surv 2001;56:361–76. [10] Nathorst-Boos J, von Schoultz B, Carlstrom K. Elective ovarian removal and estrogen replacement therapy—effects on sexual life, psychological well-being and androgen status. J Psychosom Obstet Gynaecol 1993;14:283–93. [11] Zussman L, Zussman S, Sunley R, Bjornson E. Sexual response after hysterectomy-oophorectomy: recent studies and reconsideration of psychogenesis. Am J Obstet Gynecol 1981;140:725–9. [12] Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society Position Statement. J Clin Endocrinol Metab 2007;92:405–13.