69 Endocrine Aspects of Sexual Dysfunction in Men
Alvaro Morales, MD,* Jacques Buvat, MD,?Louis J. Gooren, MD,?Andre T. Guay, MD,§
Jean-Marc Kaufman, MD,?Hui Meng Tan, MD,#and Luiz O. Torres, MD**
*Department of Urology, Queen’s Univerisity, Kingston, ON, Canada; ?Centre ETPARP, Lille, France, ?Department of Endocrinology, Vrije University, Amsterdam, The Netherlands; §Center for Sexual Function/Endocrinology, Lahey Clinic Northshore, Peabody, MA, USA; ?Department of Endocrinolgy and Rheumatology, University Hospital Ghent, Ghent, Belgium; #University of Malaya, Selangor, Malaysia; **Funcionarios Belo Horizonte, Minas Gerais, Brazil
Summary of Committee. For the complete report please refer to Sexual Medicine: Sexual Dysfunctions in Men and Women, edited by T.F. Lue, R. Basson, R. Rosen, F. Giuliano, S. Khoury, F. Montorsi, Health Publications, Paris 2004.
A B S T R A C T
Introduction.Endocrine disorders of sex steroid hormones may adversely affect men’s sexual
function.
Aim.T o provide expert opinions/recommendations concerning state-of-the-art knowledge for the
pathophysiology, diagnosis and treatment of endocrinologic sexual medicine disorders.
Methods.An International Consultation in collaboration with the major urology and sexual med-
icine associations assembled over 200 multidisciplinary experts from 60 countries into 17 commit-
tees. Committee members established speci?c objectives and scopes for various male and female
sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respec-
tive sexual medicine topic represent the opinion of experts from ?ve continents developed in a sci-
enti?c and debate process. Concerning the Endocrine committee, there were eight experts from
seven countries.
Main Outcome Measure.Expert opinions/recommendations are based on grading of evidence-
based medical literature, extensive internal committee discussion over 2 years, public presentation
and deliberation.
Results.Hypogonadism is a clinical and biochemical syndrome characterized by a de?ciency in
serum androgen levels which may decrease sexual interest, quality of erections and quality of life.
Biochemical investigations include testosterone and either bioavailable or calculated free testos-
terone; prolactin should be considered when hypogonadism has been documented. If clinically indi-
cated, androgen therapy should maintain testosterone within the physiological range avoiding
supraphysiologic values. Digital rectal examination and determination of serum prostate speci?c
antigen values are mandatory prior to therapy and regularly thereafter. Androgen therapy is usually
long-term requiring regular follow-up, frequent monitoring of blood levels and bene?cial and
adverse therapeutic responses.
Conclusions.Safe and effective treatments for endocrinologic sexual medicine disorders examined
by prospective, placebo-controlled, multi-institutional clinical trials are needed.
Key Words.Hormone Therapy; Endocrine Sexual Dysfunction; Hypogonadism; Androgens;
Andropause; T estosterone; Dehydroepiandrosterone; Sex Hormone Binding Globulin;
Prolactin
? Journal of Sexual Medicine 1743 6095
Introduction
I nterest in hormone replacement therapy (HRT) in women has been extrapolated to androgen replacement therapy in men. This paper discusses the endocrine aspects of men’s sexual dysfunction including the pathophysiology, diagnostic process and treatment modalities as well as their ef?cacy. The aim of this paper is to provide guidelines for the endocrine aspects of men’s sexual dysfunction, focusing on the relationships between hormonal alterations and sexual function. The concepts detailed are limited to those aspects pertaining to endocrine alterations related to interference with the normal sexual response in the adult man.
Aging, Hypogonadism and Sexual Function:
New Concepts
The alteration in androgen production in aging men has been scienti?cally recognized for over 70 years [1]. Interest has developed recently regard-ing the importance of this condition known as male climateric, andropause, more appropriately, androgen decline in the aging male (ADAM) or late onset hypogonadism. The term andropause, although biologically wrong, conveys the concept of emotional and physical changes that, although related to aging in general, are also associated with signi?cant hormonal alterations.
Although hypotestosteronemia is the most widely recognized and investigated hormonal alteration associated with the aging process, the production of several other hormones is also pro-foundly affected by age and may have implications in sexual function. The recommendation of the I nternational Society for the Study of the Aging Male (I SSAM) should indicate that other hor-mones besides testosterone (T) can contribute to sexual dysfunction as well as other manifestations largely attributed to hypogonadism.
While vascular problems associated with aging may be the most prominent cause of erectile dys-function (ED) [2,3] other reasons may also play a prominent causal role. High locations of the central nervous system have a direct genital con-nection to the corpus cavernosa of the penis and are of fundamental importance in the control of sexual behavior and function. Aging is associated with a progressive decline in the production of several hormones including testosterone, dehy-droepiandrosterone, thyroxine, melatonin and growth hormone [4]. Hypogonadism is associated with a decrease in sexual interest and deterioration in the quality of erectile function, both of which can be improved with androgen supplementation therapy. The therapeutic response has been explained as the result of the central and periph-eral activity of androgens.
Basic animal research provides the information integrating the concepts of decreased sexual func-tion and hormonal alterations in the aging male. In a series of investigations in rodents, Wang and her co-workers [5] have shown that hypothalamic-pituitary functional alterations may not be the major cause of male gonadal dysfunction. They found evidence of a signi?cant increase in apopto-sis in both the hypothalamus and the gonads, a dual alteration that may explain the development of hypogonadism in aging. The areas of the forebrain closely linked to the decrease in gonadotropin-releasing hormone (GnRH) due to this apoptotic process are the same or intimately related to the areas controlling the penile erection process and the synthesis and release of oxytocin (Figure 1). Similarly, peptides normally character-ized by their ability to release growth hormone (GH) were found capable of inducing penile erections when injected into the paraventricular nucleus (PVN) of experimental animals. GH pro-duction also declines in relation to advancing age. These integrated views remain speculative but are worth additional research.
Epidemiological Aspects
Global prevalence of hypogonadism in mature men can be predicted from population projections. In North America several cross-sectional and lon-gitudinal studies [6–8] have con?rmed the decline in androgen production associated with age (T able 1). It has been estimated that in the United States there are 5 million hypogonadal men but only about 5% receive treatment (Figure 2) [9]. The decline in serum testosterone (T) in the aging male population is, however, a universal phenom-enon. A comprehensive review on studies aimed at the prevalence of ED has been recently published [10].
Physiological Aspects of Hormones Involved In Sexual Function
Androgens
The hypothalamic-pituitary gonadal system is a closed loop feedback control mechanism directed at maintaining normal reproductive function [11]. The gonadal hormones have inhibitory effects on the secretion of LH and FSH. Although testos-
70Morales et al. Journal of Sexual Medicine Vol. 1, No. 1, 2004
terone, the major secretory product of the testes,is a primary inhibitor of LH secretion in men,other testicular products, including estrogens and other androgens, also inhibit LH secretion. The inhibitory effects of testosterone are both pro-duced by testosterone itself and indirectly through aromatization to estradiol. Dihydrotestosterone (DHT), a nonaromatizable androgen, also inhibits LH secretion.
I n normal males, 2% of testosterone is free (unbound) and 30% is bound to sex-hormone-binding globulin (SHBG) with high af?nity [12].The remainder is bound with much lower avidity to albumin and other proteins. The fraction of T not bound to SHBG makes up the measure known as bioavailable T . These binding proteins regulate
androgen function. It is now known that albumin-bound testosterone is also available to transfer into target tissue in the brain and liver. SHBG has a higher af?nity for testosterone than for estradiol,and changes in SHBG reduce or amplify the hormonal milieu. Elevated estrogens, thyroid hormone and healthy aging will increase plasma SHBG and therefore decrease the “free” testos-terone fraction as it is the case in the elderly (Figure 3).
Androgens have a key role in both stimulating and maintaining sexual function in men. It appears
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Figure 1Hormone pulses.
Table 1Prevalence of hypogonadism in older males
Baltimore
Age (years)Longitudinal Study*Mayo Clinic ?Canadian MDs ?40–4922250–59963060–6934204570–7968347080+
91
—
—
*Based on a free androgen index.?
Based on bioavailable testosterone.
Adapted from J. Morley [34,36].
Fi gure 2Estimated prevalence of hypogonadism in the U.S.
that testosterone is necessary for normal libido,
ejaculation and spontaneous erections. There is a
threshold with individual variation, below which sexual function is impaired [13]. t has been reported that androgens are important in the expression of neuronal NOS and in the expression of the phosphodiesterase-5 (PDE-5) gene expres-sion [14].An animal model showed that normal androgen levels are a prerequisite for a PDE-5inhibitor (vardena?l) to work appropriately, and that androgen deprivation leads to fundamental structural alterations in the corpus cavernosa resulting in failure of the veno-occlusive mecha-nisms [15].
The most prominent concern about androgen use relates to prostate safety. Androgens, speci?-cally dihydrotestosterone, are necessary for benign prostatic growth. There is a majority consensus that testosterone administration does not cause prostate cancer. I t is also commonly agreed that subclinical prostatic adenocarcinoma may become manifest rapidly after androgen therapy. None of the published studies [16,17] have included suf?-cient number of men or have adequate follow-up,therefore de?nitive answers are not yet available.The Sexual Medicine Society of North America, adopted the following Position State-
ment at its annual meeting in April 2003: “T estos-terone supplementation is indicated for men who have signs and symptoms of hypogonadism accompanied by subnormal serum testosterone measurements. T estosterone supplementation can provide important health bene?ts to these hypog-onadal men. T estosterone supplementation should be administered only under competent and careful medical surveillance in order to identify early signs of possible adverse effects. Although the bene?ts and risks of long-term testosterone supplementa-tion have not yet been de?nitively established, the weight of current evidence does not suggest an increased risk of heart disease or prostate cancer with long-term use of testosterone. T estosterone is not medically indicated in men who do not have hypogonadism.” It is a reasonable position on the relevant issues of cardiovascular and prostate health, pending de?nitive studies.
The adrenal androgens are dehydroepiandros-terone (DHEA), its sulphate (DHEA-S) and androstenedione. Their androgenic action is much weaker than that of testosterone which is weaker than DHT (T able 2). The adrenal androgens convert to other sex steroids such as testosterone,estrone and estradiol, mainly locally in tissues (Figure 4). Their contribution to circulating levels of testosterone in adult men and to estrogens in women is, however, insuf?cient to prevent hypog-onadism in cases of gonadal failure. The relative potency of DHEA in relation to other sex steroids is illustrated in T able 2.Adrenal androgens are produced in abundant quantities, but the produc-tion declines steadily in an age related fashion (Figure 5).
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Figure 3T partition in young and old men.
Table 2Potency of various sex steroids, taking testos-terone at a relative value of 100
Relative activity of androgens ?Dihydrotestosterone 300?Testosterone 100?Androstenedione 10?
DHEA, DHEAS
5
Figure 4Adrenal androgen metabolism.
Until recently DHEA was considered only as a pre-hormone exerting indirect androgenic and estrogenic effects following its peripheral conver-sion into small amounts of testosterone and estra-diol. This physiological conversion indicates that DHEA administration may carry the same risks as testosterone or estradiol. Since DHEA and its sul-phated form are freely interconverted by extra-adrenal sulphotransferase and sulphatase activities,DHEA-S constitutes a large plasma reservoir of DHEA (Figure 4).
Our understanding of DHEA is changing due to the identi?cation of a putative speci?c DHEA-receptor on the plasma membrane of bovine aortic endothelial cells [18]. This receptor is functionally coupled to the G protein family, primarily to G-12 and G-13 subtypes. Activation of these G pro-teins promotes the production of endothelial nitric oxide synthase (eNOS). The putative DHEA receptor resembles the plasma membrane estro-gen receptor but estrogens and anti-estrogens do not alter either the binding of DHEA to this new receptor or its effects on eNOS production. This discovery opened the way to the concept of an intracellular receptor since all major steroid hor-mones in which plasma membranes receptors have been reported also have well characterized intra-cellular receptors. A further recent study by Williams et al. [19] brought up evidence support-ing the existence of a DHEA-speci?c receptor in human vascular smooth muscle cells (VSMC),involving ERK 1 signaling pathways: VSMC pro-liferation contributes to remodeling of blood vessels, and may be implicated in the pathogene-sis of atherosclerosis. This proliferative process,which is inhibited by estradiol and stimulated by testosterone, is inhibited in vi t ro by DHEA.Although not negating the mechanism of action through conversion into testosterone and estra-diol, these ?ndings will have a fundamental impact
on our interpretation of the biological actions of DHEA. This may be especially relevant in regards to sexual function that involves many vascular mechanisms in both men and women.
Hypothalamic-Pituitary-Thyroid Axis
Aging-related changes in the hypothalamic-pituitary-thyroid axis include a decrease in pitu-itary thyrotropin (TSH) to thyrotropin releasing hormone, diminished response to the thyroid to TSH and decreased serum concentration of total or free T3 and T4. These changes and the increas-ing prevalence, with age, of autoimmune thyroid diseases may result in the development of hypothyroidism, however this does not usually affect erectile function. Hyperthyroidism, on the other hand, increases the levels of SHBG and increases the aromatization of testosterone into estrogen. These two events may have detrimental effect on sexual function.
Prolactin has no known de?nitive role in the physiological control of human sexual behavior,however hyperprolactinemia can inhibit most of aspects of male sexual behavior. Buvat et al. [20],in a study of 300 men with hyperprolactinemia,found the most common sexual manifestation was a decrease in erectile function associated with a marked reduction in sexual interest. Delayed or absent orgasm was also found but virtually never as an isolated symptom. Some cases of retro-grade ejaculation were also reported. Many cases result from pituitary adenomas likely to result in serious endocrinologic, visual and neurologic complications.
Hyperprolactinemia impairs the pulsatile LH secretion, which, in turn, produces a decline in serum testosterone production by the gonads. The resulting hypogonadism is generally thought to be the main cause of erectile dysfunction. Serum testosterone is in the low normal range in nearly half of the men with marked hyperprolactinemia and erectile dysfunction. I n addition plasma sex hormone-binding globulin is lowered in hyper-prolactinemic males [21], which attenuates the effects of low serum total testosterone by increas-ing the proportion of unbound testosterone.Moreover, during treatment of hyperprolactine-mic men with the dopamine-agonist bromocrip-tine, sexual improvement correlates better with the decrease of serum prolactin than with the increase of the testosterone level. It is not uncom-mon that these men report a return of their erec-tions prior to any increase in serum testosterone.
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Fi gure 5Pattern of DHEA-S decline in production as a function of age in men and women.
Other studies, including that of Bancroft et al.
[22], who compared bromocriptine with a placebo
a double blind design in a single man, tend to support the hypothesis of a direct, testosterone independent, effect of prolactin on sexual behav-ior of men.
The mechanisms independent of the circulating level of testosterone may be related to a decrease in the 5-alpha reduction of testosterone to dihy-drotestosterone, reported by Lobo and Kletzky [23] in hyperprolactinemic men. Prolactin incre-ases the synthesis, turnover and release of central dopamine from neurons of the hypothalamus [24].
The prevalence of hyperprolactinemia was very low (1 to 5%) in men referred for erectile dys-function [25–30]. The prevalence of mild hyper-prolactinemia was 1.5% in a series of 1370 consecutive ED patients [31]. I t is unlikely that such modest hyperprolactinemias are the real cause of the ED.Erectile function improves 40% following the administration of the dopaminergic agonist bromocriptine, similar to normopro-lactinemic men with ED [32]. The ef?cacy of bromocriptine alone in cases of ED with serum prolactin greater than 35ng/mL suggests a causative effect.
Insulin and Diabetes Mellitus
The most prominent endocrine cause of sexual dysfunction is diabetes mellitus (DM). The primary organic, pathophysiological factors causing ED in diabetics can be categorized as neuropathic and vascular. Diabetes lowers testos-terone: hypogonadism may be yet another factor contributing to ED in this population. Low testos-terone levels and elevated gonadotropins were found in a large observational study, but only in the population of diabetic men with neuropathy [33]. The MMAS longitudinal epidemiological study of 1,709 men found that testosterone and SHBG levels were predictive of new cases of diabetes [34].
Diagnosis of Hypogonadism
A diagnosis of hypogonadism in men should always be based on both a suggestive clinical picture and the biochemical demonstration of hypoandrogenism. The syndrome of late onset hypogonadism in men is characterized clinically by: 1. the easily recognized features of diminished sexual desire and erectile quality, particularly noc-turnal erections; 2. changes in mood with con-comitant decreases in intellectual activity, spatial orientation ability, fatigue, depression and anger;
3. decrease in lean body mass with associated diminution in muscle volume and strength;
4. decrease in body hair and skin alterations;
5. decreased bone mineral density resulting in osteo-porosis;
6. increase in visceral fat. These manifes-tations need not all be present to identify the syndrome. In addition, the severity of one or more of them does not necessarily match the severity of the others, nor do we yet understand the uneven appearance of these manifestations [35]. In prac-tice, the clinical diagnosis may be facilitated with the use of screening questionnaires. Validated ones are currently available for screening men sus-pected of hypogonadism [36,37]. The ADAM questionnaire is a simple and sensitive question-naire but performs marginally on speci?city, par-ticularly in the elderly. I t is, however, useful for its purpose of initial screening, leading to a bio-chemical assessment (T able 3, 3a). A more exten-sive, validated instrument, the Aging Male Scale (AMS), is also available (T able 4). Neither of these questionnaires replaces a proper history and phys-ical examination [38].
I t is important to realize that even the most sophisticated biochemical measures of serum androgens can be at best an approximation of the androgen status. Such a measure does not take into account the role of intratissular metabolism of androgens into bioactive metabolites (“intracrino-logy”), or interindividual differences in androgen sensitivity, the so-called “endocrine disruptors.”
Sex hormone binding globulin (SHBG) increases, associated with advancing age (Figure 3), which translates to a decrease in bioavailable (free and albumin-bound fractions) testosterone [39]. An additional phenomenon associated with aging is the ?attening of the circadian rhythm leading to steady low levels of androgens through-out the 24 hour cycle [40]. There are three impor-tant areas that require further elucidation: a) abnormal serum T levels in men over 50 (when ED becomes most prevalent), although two stan-dard deviations below normal values for young men is generally accepted as de?cient; b) variable responses by the target organs to the levels of androgens; and c) the in?uence of endocrine dis-ruptors on target organ response. The combina-tion of these three uncertainties is important: Androgen de?ciency may become clinically appar-ent at different points within an individual or a population, depending on the marker used.
There are several reasons to justify basic hor-monal assessment of men with sexual dysfunction.
74Morales et al. Journal of Sexual Medicine Vol. 1, No. 1, 2004
It is commonly accepted that the combination of low sexual desire and erectile dif?culties may be the result of hormonal abnormalities. T estos-terone levels required for normal sexual function may be below the physiological range [41]. Rec-ommendations of biochemical investigations for patients with sexual dif?culties who are at risk or suspected of hypogonadism include the following:a) measure serum T between 8:00 and 11:00 am,the best parameter being bioavailable T; and b) if T levels are below or at the lower limit of the accepted normal values, con?rm the results with a second determination together with assessment of luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin. I n the younger (<40 years) male, low levels of T (<12nmol/L or <350ng/dL) with chronically elevated gonadotro-pins means a clear diagnosis of primary hypogo-nadism or testicular failure.
Vermeulen [42] emphasized that there is no generally accepted cut off value of plasma testos-terone to unambiguously de?ne androgen de?-ciency. In the absence of convincing evidence for an altered androgen requirement in men at differ-ent ages, he considers the normal range of free T levels in young males is also valid for elderly men.If one takes as lower normal limit and threshold of partial androgen de?ciency a conservative value of 11nMol/L for T and 0.225nMol/L for FT ,which represent the lower 1% value of healthy young males, then it appears that more than 30%of men over 75 years old have subnormal (F)T levels [43–46].
Although total T measurements can be mis-leading, assessment of free T (FT) provides a more reliable index of androgenicity. The confusion arises on the methodologies used to measure FT .Direct FT assays using a testosterone analogue (FT ra) do not yield reliable estimates of FT . Reli-able assays for FT are equilibrium dialysis (FTd)and ultracentrifugation (FT u). These two are more dif?cult to perform and not widely used clinically.Bioavailable T by ammonium sulphate precipita-tion is more commonly accessible, reliable and less expensive. The calculated FT (cFT) is widely available, reliable and inexpensive. The cFT can be calculated using the formula described by Vermeulen et al. [47]and readily available from
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Table 3
Format and interpretation of the ADAM screening questionnaire
a.
ADAM Screening Questionnaire
(For male patients over 40 years of age)Please print:
Name _____________________________________Date of Birth __________________________________
Month /Day /Year
Please check:
“Yes ”or “No ”1.??Do you have a decrease in libido (sex drive)?2.??Do you have a lack of energy?3.??Do you have a decrease in strength and/or endurance?4.??Have you lost height?5.??Have you noticed a decrease in “enjoyment of life”?6.??Are you sad and/or grumpy?7.??Are your erections less strong?8.??Have you noted a recent deterioration in your ability to play sports?9.??Are you falling asleep after dinner?10.??Has there been a recent deterioration in your work performance?b.
How to Evaluate ADAM Questionnaire (Androgen De?ciency in the Aging Male)
INTERPRETATION of completed ADAM Questionnaire Further investigation should include a laboratory assay for:Bioavailable testosterone or, alternatively
a “non-age-adjusted” free testosterone
the web page of the International Society for the Study of the Aging Male [48].
Treatment of Hormonal Abnormalities
Hormone replacement therapy aims to substitute the de?cient hormone with a perfect copy of the natural hormone, with a dose schedule that gen-erates physiological hormone levels over 24 hours of the day. A decision tree for long-term androgen treatment of the adult male with androgen de?-ciency is shown on Figure 5.I t summarizes in a practical way the views in the text.Though subcutaneous testosterone implants [49], transdermal patches [50], and more recently the transdermal gel constitute veritable improve-ments, the pharmacokinetics and pharmacody-namics of the more traditional forms of androgen replacement fail to mimic the serum androgen pro?les produced by the testis. This situation is re?ected by the side effects of androgen administration which may result from the modes of testosterone replacement leading to non-physiologically high/low levels of testosterone/5a -dihydrotestosterone (DHT) or the aromatiza-tion product estrogen and their ratios. In addition,
the route of administration matters; transdermal
administration of testosterone is associated with high DHT levels. Most commonly available test-osterone commercial formulations are listed in T able 4.The available studies in hypogonadal men show that dihydrotestosterone (DHT) maintains sex char-acteristics, increases muscle mass and improves sexual functions without signi?cant increases in prostate size [51]. DHT gel is available at a dose of 125–250mg/d, which yields plasma DHT levels comparable to physiological T levels.
Estrogens, conceptualized as “female hor-mones,” have been considered detrimental to male sexual function. Estrogen receptor knockout mice show abnormalities of the testis and accessory sex organs [52]. In view of the effects of estrogen on many important organ systems in the male, further
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Table 4
Aging males’symptoms (AMS) scale
Intensity of symptom (points)
No Mild Moderate Severe Very severe Symptom
123451.Deterioration of general well-being
?????(health status and perceived general situation)https://www.doczj.com/doc/fc7334538.html,plaints in joints or muscles ?????(pain in lower back, joints or legs)
3.Sweating (eruptions of sweat, hot ?ushes)?????
4.Sleep disturbances
?
?
?
?
?
(falling asleep, continuing to sleep, waking too early or tired,sleepiness)
5.Increased need for sleep ?????(often tired)
6.Irritability
?????(ill-humored, irritated by minor causes, become angry or cross easily)7.Nervousness
?????(inner tension, unrest, unable to stay calm and relaxed)8.Anxiety ?????(panic)
9.Exhaustion/decreased energy
?
?
?
?
?
(general limitation of performance, reduced activity, less interest to do something, perceived low achievement, need for unusual stimulation to be active)
10.Decrease in muscular strength
?????(weakness)
11.Depressed mood
?
?
?
?
?
(discouraged, sad, tearful, less drive, frequent changes of mood,feeling of senselessness)
12.Feeling to have passed zenith of life
?????13.Wish to be dead, arrived at dead point, totally discouraged ?????14.Decrease in beard growth ?????15.Decrease in potency
?????16.Decrease in frequency or morning erections ?????17.Decrease in libido and sexual activity
?????
(desire for sex, interest in sex)
Date: ______________
Patient Initials: ______________
Patient Number: ______________
research into the role of estrogens is necessary. Since androgens are the precursors of estrogens and the main production of estrogens in men is in peripheral organs, part of exogenously adminis-tered testosterone is aromatized to estradiol. The rise in plasma estradiol levels following adminis-tration of testosterone lies somewhere between 50 and 150%. In other words, supplementing testos-terone implies also supplementing estradiol.
The therapeutical potential of SERMs in women may set the stage for the development of selective androgen receptor modulators (SARMs). The availability of these molecules with their diversity of ligands provides the opportunity to explore the utility and activities of SARMs [53].
Measuring 17 hormones, DHEA-S was the only one that strongly and inversely correlated with the prevalence of ED in the Massachusetts Male Aging Study (MMAS). The most compre-hensive, long-term study on DHEA supplementa-tion in aging men was reported by Baulieu et al.
[54] in a double blind placebo controlled study of 140 men receiving either 50mg of DHEA or a placebo daily. No signi?cant difference between the DHEA and placebo groups was found. Serum estradiol, but not serum testosterone, signi?cantly increased on DHEA. No effect on different meas-ures of well-being was observed.
Only one study has monitored the effects of 3 months administration of human chorionic gonadotropin to aging men with plasma testos-terone levels in the lower range of normal [55]. Plasma levels of total and free testosterone and estradiol increased 50% above baseline. The effects were very similar to those of androgen administration to aging men.
It is common clinical practice to judge the ade-quacy of androgen replacement by the effects on general well-being, mood, sexual interest and sexual activity. Recent reports suggest a marginal syner-gistic effect on ED when testosterone is added to phosphodiesterase inhibitors in hypogonadal men who had failed the latter as a single therapy [56,57], apparently mediated by an increase in?ow in the cavernosal arteries [58]. A general principle in hormone replacement therapy is that plasma levels to be achieved over the 24 hours of the day must come close to normal reference values, and ideally follow the normal diurnal pattern. Recommendations
1.De?nition: Adult onset hypogonadism is a
clinical and biochemical syndrome frequently
associated with advancing age and character-ized by a de?ciency in serum androgen levels, with or without changes in receptor sensitiv-ity to androgens. It may affect the function of multiple organ systems and result in signi?-cant detriment in the quality of life, including major alterations in sexual function.
2.Clinical diagnosis:The clinical manifestations
of adult hypogonadism are not speci?c. Sexual dysfunction (decrease in sexual interest and quality of erections) is prominent, and often the presenting symptom. Depression, irri-tability, cognition and sleep, as well as dimin-ished strength and endurance may also be present. The physical examination is fre-quently unhelpful, but alterations in testicu-lar size and consistency, hair distribution, muscle mass, body shape and sequelae of osteoporosis can be detected. Not all the man-ifestations need to be evident simultaneously and their intensity shows marked interindi-vidual variability.
3.Biochemical diagnosis:I n patients with sexual
dysfunction, testosterone (T) and either bioavailable or calculated free T are the biochemical investigations recommended.
T estosterone should be measured between 8:00 and 11:00 am. The most accessible and reliable assays to establish the presence of hypogonadism are the measurement of bioavailable T or the calculated free T (cFT).
Assays for total testosterone, particularly in the elderly, may not re?ect the man’s true androgenic status. If T levels are below or at the lower limit of the accepted normal values, it is prudent to con?rm the results with a second determination together with assess-ment of luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin.
4.Prolactin:Hyperprolactinemia is an uncom-
mon cause of ED, however, determination of serum prolactin is recommended in cases associated with diminished sexual interest and when biochemical hypogonadism has been documented.
5.Other hormonal alterations besides sex hormones:
It is recognized that signi?cant alterations in other endocrine systems occur in association with aging but the signi?cance of these changes is not well understood, particularly in relation to sexual function. In general terms, determinations of estradiol, DHEA, DHEA-S, melatonin, GH and I GF-1 are not indi-cated in the uncomplicated evaluation of
Endocrine Aspects of Sexual Dysfunction in Men77 Vol. 1, No. 1, 2004Journal of Sexual Medicine
hypogonadism. Under special circumstances
or for well-de?ned clinical research, assess-
ment of these and other hormones may be
warranted.
6.Diabetes:Diabetes mellitus is a frequent
endocrinologic cause of erectile dysfunction.
I t should be ruled out in men complaining
of sexual inadequacy. Appropriate glycemic
control is fundamental before consideration of
any other hormonal treatment in men with
ED.
7.Lipids:A lipid pro?le should be considered as
a relevant option in the initial assessment of
men with erectile dysfunction.
8.Indicat ions for t herapy:A clear indication (a
clinical picture together with biochemical evi-
dence of hypogonadism) should exist prior to
initiation of androgen therapy.
9.Age:I n the absence of de?ned contraindica-
tions, age is not a limiting factor to initiate
ART in aged men with hypoandrogenism. 10.Sexual funct ion:Hypogonadal men with spe-
ci?c sexual dysfunctions (e.g., ED and/or
diminished interest) are candidates for andro-
gen therapy. Absence of an adequate response
after appropriate testosterone treatment calls
for further investigation to rule out associated
comorbidities.
https://www.doczj.com/doc/fc7334538.html,bined treatment for erectile dysfunction:Evi-
dence is emerging suggesting therapeutic synergism with combined use of testosterone
and phosphodiesterase-5 inhibitors in hypo-
gonadal or borderline eugonadal men. These
observations are very preliminary and require
additional study. However, the combination
treatment can be considered in patients failing
adequate treatment with phosphodiesterase
inhibitors alone. No credible evidence for or
against exists with other drugs in combination
with androgens.
12.T estosterone commercial formulations:Currently
commercially available preparations of testos-
terone (with the exception of the alylated
ones) are safe and effective. The treating
physician should have suf?cient knowledge
and adequate understanding of the advantages
and drawbacks of each preparation. The
patient should be given the opportunity to
actively participate in the choice of androgen
formulation.
13.Serum levels:The purpose of ART is to bring
and maintain serum T levels within the phys-
iological range. Supraphysiologic levels are to
be avoided. Although it may appear desirable,
no evidence exists for or against the need to
maintain a circadian rhythm of serum T
levels.
14.Other androgens:The use of DHEA and DHT
has not been proven to be effective speci?cally
in male sexual dysfunction. Current evidence
on DHT ef?cacy is also insuf?cient. There is
a need for additional studies aimed expressly
at investigating the effects of these hormones
on sexual function.
15.Androgen abuse:Androgens should be used
only when speci?c indications exist. Their
(ab)use for performance enhancement, in the
absence of hypogonadism, is to be condemned
in the strongest terms.
16.Monitoring—liver:Currently available T
preparations are largely free of hepatic toxic-
ity (methylated forms are an exception). Liver
function studies are advisable prior to onset of
therapy. Periodic assessment during treatment
may be considered. Despite the lack of evi-
dence, commercial manufacturers (for regula-
tory purposes) include warnings about hepatic
risks in their product insert.
17.Monitoring—lipids:A fasting lipid pro?le prior
to initiation of treatment, if not done as part
of the initial evaluation (Recommendation 7)
and re-assessment at 3 or 6 months after onset of testosterone administration is also
recommended.
18.Monitoring—prostate:I n men over the age of
40 years, digital rectal examination (DRE) and
determination of serum prostatic speci?c
antigen (PSA) are mandatory as baseline
measurements of prostate health prior to
therapy with androgens, every three (3) to six
(6) months for the ?rst 12 months, and yearly
thereafter. T ransrectal ultrasound guided
biopsies of the prostate are indicated only if
the DRE or the PSA are abnormal.
19.Prostate and breast safety—I:Androgen admin-
istration is absolutely contraindicated in men
suspected of harboring carcinoma of the
prostate or breast.
20.Prost at e safet y—II: Men successfully treated
for prostate cancer and suffering from symp-
tomatic hypogonadism may become candi-
dates for androgen therapy, after a prudent
interval, if there is no evidence of residual
cancer. The risk and bene?ts must be clearly
understood by the patient and the follow-up
must be particularly careful. No reliable evi-
dence exists in favor or against this recom-
mendation. The clinician must exercise good
78Morales et al. Journal of Sexual Medicine Vol. 1, No. 1, 2004
clinical judgment together with adequate
knowledge of the advantages and drawbacks of
androgen therapy in this situation.
21.Pros a e safe y—III:Androgen supplementa-
tion is contraindicated in men with severe
bladder outlet obstruction due to an enlarged,
clinically benign prostate. Moderate obstruc-
tion represents a partial contraindication to
ART. After successful treatment of the
obstruction, the contraindication can be lifted.
22.Monitoring—mood:Androgen replacement
therapy normally results in improvements in
mood and well-being. The development of
negative behavioral patterns (aggressiveness,
hypersexuality) during treatment calls for dose
modi?cations or discontinuation of therapy. 23.Monitoring—hematology:Polycythemia may
develop during ART. Periodic hematologic
assessment is indicated. Dose adjustments,
change of preparation, periodic phlebotomies
or discontinuation of treatment may be necessary.
24.Monitoring—sleep apnea:Exacerbation of sleep
apnea may occur during testosterone supple-
mentation therapy. Proper assessment and
treatment of the sleep apnea are indicated
during testosterone supplementation. Careful
consideration should be given to the need for
testosterone treatment if the sleep distur-
bances deteriorate.
25.Physician’s responsibili ies:Androgen replace-
ment therapy is normally for life. This
demands a life commitment for follow-up.
The treating physician must be familiar with
the diagnostic, therapeutic and monitoring
aspects of androgen therapy. Good clinical
judgment is equally important. I nadequate
therapeutic response, or the appearance of
signi?cant adverse effects, calls for re-
assessment of treatment indications.
Corresponding Author: Alvaro Morales, MD, Department of Urology, Queen’s University, 76 Stuart St, Kingston, Ontario, Canada K7L 2V7. T el: (613) 548-2424; Fax: (613) 545-1970; E-mail: moralesa@post.queensu.ca
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