Chapter 19 – Androgen Therapy for Postmenopausal Women




Abstract




Traditionally, the term androgens refers to a group of 19 carbon steroid hormones that are associated with maleness and the induction of male secondary sexual characteristics. This is as outdated as the concept of estrogen being only a female hormone. The major androgens circulate in concentrations greater than those of the estrogens in healthy women and androgens have a critical role in female physiology.





Chapter 19 Androgen Therapy for Postmenopausal Women



Susan R. Davis



What Is Androgen Therapy and Why Is It Sometimes Prescribed?


Traditionally, the term androgens refers to a group of 19 carbon steroid hormones that are associated with maleness and the induction of male secondary sexual characteristics. This is as outdated as the concept of estrogen being only a female hormone. The major androgens circulate in concentrations greater than those of the estrogens in healthy women and androgens have a critical role in female physiology.


Testosterone is the main androgen in women, with its more potent metabolite, dihydrotestosterone (DHT), being important at a cellular level. The steroids androstenedione and dehydroepiandrosterone (DHEA) are classified as preandrogens, although each exhibits very weak binding to the androgen receptor. Androstenedione and DHEA are produced by both the ovaries and the adrenals, whereas DHEA sulfate (DHEA-S) is almost exclusively a product of the adrenal glands. Dehydroepiandrosterone is a precursor for androstenedione production, which in turn can be converted to testosterone or estrone. There is increasing interest in the possible clinical importance of oxygenated C19 steroids, 11-ketestosterone (11-ketoT) and 11-ketoDHT, which are formed peripherally from the adrenal hormones 11-hydroxytestosterone and 11-androstenedione [1]. 11-ketoT and 11-ketoDHT appear to bind and activate the androgen receptor in a manner similar to that of testosterone and DHT, respectively; however, the role of these hormones in female physiology and pathophysiology is yet to be determined [1].


Androgen therapy in clinical practice refers to testosterone therapy, although DHEA is sometimes included under this heading. Androstenedione has been used as a body-building supplement, but its use as such is banned by the Food and Drug Administration of the US and international sporting bodies because of safety concerns.


There is widespread prescription of DHEA as androgen therapy for women. Clinical trials have consistently shown that systemic DHEA therapy is not effective for the treatment of female sexual dysfunction (FSD) in women with either normal or impaired adrenal function, and should not be prescribed for this purpose [2]. Dehydroepiandrosterone does not improve mood or cognitive function in healthy women. Dehydroepiandrosterone may improve the health-related quality of life and mood in women with adrenal insufficiency, although these effects have been described as trivial [3]. There are preliminary data that daily intravaginal DHEA may alleviate vulvo-vaginal atrophy, but this requires confirmation in larger studies.


Tibolone is a synthetic compound that is used as a postmenopausal hormone therapy. It is metabolized in the gut and target tissues to isomers that exhibit estrogenic, progestogenic and androgenic actions. It therefore alleviates vasomotor symptoms and urogenital atrophy but does not activate the endometrium, and so does not cause vaginal bleeding. An active metabolite of tibolone has weak androgenic action. As a result, tibolone may improve libido and arousal [4]. As tibolone is a menopausal hormone therapy, not a specific androgen therapy, it is not discussed further in this chapter. The remainder of this chapter focuses on testosterone therapy for postmenopausal women as this is the androgen therapy with a sound evidence base and the most widely used.


The primary indication for the use of testosterone therapy is for the treatment of FSD, specifically, desire-arousal disorder. Initially loss of sexual desire associated with personal distress was classified as ‘hypoactive sexual desire disorder’ in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM–IV) [5]. Since it has been established that low sexual desire and low arousal are co-dependent, the two have been combined in DSM–5 as ‘desire-arousal disorder’ [6]. However, the global consensus, indicated by the International Classification of Disease 11th Revision, is that low desire and arousal dysfunction should remain as separate clinical entities [7]. Pivotal to the diagnosis of either sexual desire or arousal dysfunction is that the woman must be sufficiently bothered by the problem that it causes her some degree of distress. In clinical practice this usually translates to a woman presenting for treatment, although there is probably a large number of women troubled by low desire or low arousal who, for a range of reasons, never raise this concern with a health care provider. Treatment of a desire or arousal dysfunction may involve relationship and/or sexual counselling, or it may involve a trial of testosterone therapy. Although testosterone therapy may have other favourable effects, the evidence is not strong enough for its use for any indication other than the treatment of sexual desire dysfunction at this time.



Basic Androgen Physiology


In women, androgens exert direct actions through the androgen receptor in a range of tissues. They have anabolic actions on bone and muscle, are important for normal sexual hair growth and skin sebum production, act in the cardiovascular system with positive effects on vascular endothelial function, and influence sexual function, mood and cognitive performance.


As androgens are obligatory precursors for the production of estradiol and estrone, these steroids can be considered to exert indirect actions through the estrogen receptors. For example, an adequate intra-ovarian testosterone concentration is essential for normal cyclical follicular development.


Blood levels of testosterone and androstenedione vary across the menstrual cycle, being lowest during the early follicular phase and rising to a peak by mid-cycle. The levels then fall slightly, and remain at a plateau across the luteal phase, falling to a nadir after the onset of menstruation [8]. Testosterone may have a diurnal variation in young women in the follicular phase, with levels peaking between 0400 and midday [9]. In contrast, the levels of DHEA and DHEA-S are fairly constant across the cycle. The physiology of the ketoandrogens remains uncertain, but as adrenal products they are unlikely to change by menstrual cycle phase.


The levels of testosterone, DHT, DHEA-S, DHEA and androstenedione decline in women from the mid twenties through to the late forties, do not change across the natural menopause transition, but decline slowly with age thereafter [10]. The mechanism underpinning the decline in androgens during the reproductive years is not known, but may reflect ovarian aging.


An important aspect of testosterone physiology is that two-thirds of circulating testosterone is bound to sex hormone binding globulin (SHBG), with the remainder bound to albumin, such that only 1–2 per cent of testosterone circulates unbound to protein. As a consequence the concentration of SHBG determines how much testosterone circulates unbound. Whether this is important has been called to question in recent years. It was believed that the unbound fraction of testosterone exerts physiological effects. However, contrary to this belief the unbound fraction might be the most vulnerable to degradation and it may be SHBG-bound testosterone that is of greatest importance [11]. Women with higher SHBG levels have lower free testosterone and vice versa.



When Are Androgen Levels Low in Women?


Most women will experience a significant age-related fall in androgen levels before they reach menopause. In addition, several spontaneous and iatrogenic conditions may cause abnormally low androgen levels.


Spontaneous causes of androgen insufficiency include:




  • primary ovarian insufficiency



  • hypothalamic amenorrhea



  • hyperprolactinaemia (which can also be iatrogenic)



  • adrenal insufficiency (due to loss of DHEA, DHEA-S and androstenedione production)



  • panhypopituitism.


Iatrogenic causes of androgen insufficiency include: surgical menopause at any age




  • chemotherapy



  • radiotherapy to the pelvis



  • systemic glucocorticosteroid therapy (suppression of adrenal preandrogen production) oral estrogen, as the contraceptive pill or as menopausal hormone therapy, and exogenous thyroxine increase SHBG and lower a woman’s free testosterone level.



Testosterone Therapy



How Is Testosterone Administered and Is It Effective for the Treatment of FSD?


The early studies of testosterone for the treatment of FSD used oral methyltestosterone with oral estrogen. These trials showed efficacy at the expense of lowering HDL cholesterol, apolipoprotein A1, apolipoprotein B, LDL particle size and increasing total body LDL catabolism. Other early studies involved the use of subcutaneously implanted testosterone pellets. Similarly these are highly effective, but they require a minor surgical procedure, the dissolution rate varies substantially between women, careful monitoring is required and their availability is limited.


The most extensively studied testosterone therapy for women has been a transdermal testosterone patch, which is changed twice a week, and releases approximately 300 µg of testosterone per day. The studies of this therapy have involved over 3000 women who have received active treatment for hypoactive sexual desire dysfunction (HSDD).


The transdermal testosterone patch significantly improves desire, arousal, orgasm frequency, sexual satisfaction and pleasure compared with placebo in postmenopausal women using oral or transdermal estrogen, or not on any estrogen therapy who present with HSDD. Most recently it has also been shown to increase the number of self-reported satisfactory sexual events in women with antidepressant-associated FSD. The transdermal testosterone patch was approved for use in Europe, but approval was limited to surgically menopausal women with persistently low libido despite adequate estrogen therapy. As the uptake in Europe was low, and the European regulators refused to broaden the indication for use, the patch was withdrawn from the market. Other transdermal testosterone formulations for women, including a transdermal gel and a skin spray, with demonstrated efficacy, have not progressed through the approval process. A transdermal 1 per cent testosterone cream for women is available in Australia. It has been shown to be effective and to have consistent pharmacokinetic properties in small studies.


Testosterone undecanoate, in a dose of 40 mg either daily or on alternate days, is used in many countries. Unfortunately this compound has highly variable absorption and can result in levels in the normal male range. Oral testosterone undecanoate also adversely affects lipoproteins and increases insulin resistance. Compounded testosterone implants are used by some physicians to treat women. These lack evidence of efficacy and safety and may expose women to risk of virilization.


Fundamentally, the lack of an approved testosterone formulation for women in most countries leaves many physicians with no choice but to prescribe male formulations off-label, or recommended compounded testosterone creams or lozenges. None of these approaches can be considered safe.

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Sep 9, 2020 | Posted by in GYNECOLOGY | Comments Off on Chapter 19 – Androgen Therapy for Postmenopausal Women
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