AGE-RELATED HYPOGONADAL SYNDROME: (ANDROPAUSE/ADAM/PADAM)
Terminology and Definitions
“Hypogonadism” refers to the consequences of diminished function of the gonads; occurs at any age and for a variety of reasons; and is classified into two forms on the basis of the source of the problem, that is, either of testicular origin, or as a result of disorder in the hypothalamic-pituitary axis (Fig. 4.3). Sex-related phenomena associated with hypogonadism are described in the “Hormones” section of this chapter.
The term “andropause” indicates a particular type of hypogonadism that is related to aging in men and is said to consist of the following: diminished sexual desire and erectile function, decrease in intellectual activity, fatigue, depression, decrease in lean body mass, skin alterations, decrease in body hair, decrease in bone mineral density resulting in osteoporosis, and increase in visceral fat and obesity (24). The word andropause is an attempt to draw a parallel in men to the experience of menopause in women. Whereas menopause occurs abruptly, andropause is said to occur quite slowly. As well, menopause is associated with the irreversible end of reproductive life, whereas in men spermatogenesis and fertility continue into old age. In the opinion of some observers, trying to equate the two is rather questionable (23).
The existence of andropause is a subject of controversy partly because of great difficulty distinguishing this syndrome from age-related confounding vari- ables such as nonendocrine illnesses (both acute and chronic diseases), poor nutrition (inadequate or excessive food intake), smoking, alcohol use, and medi- cations (24,48). Some observers have less doubt about the existence of a disorder but prefer to use a different name: ADAM (androgen decline in the aging male) (49), or PADAM (partial ADAM which refers to androgen decline that is still within the normal range).
To underline the fact that many hormones decline with age, the word “adre- nopause” has also been used to describe the diminution of the adrenal androgens DHEA and DHEAS (see section titled “hormones”), and “somatopause” to describe the same in the somatotrophic hormone, growth hormone (GH).
Given that andropause/ADAM/PADAM is purported to be one form of hypo- gonadism, the phenomena described under “Assessment” above in this chapter, applies here as well.
Low sexual desire is usually seen as a symptom of andropause/ADAM/ PADAM. To explain the desire change, a great deal of emphasis has been given to laboratory values, especially alterations in T. However, the typical history has received much less attention. Only one study of aging men seems to have examined various manifestations of sexual desire. Schiavi et al. reported on 77 volunteer couples who responded to an announcement concerning a exam- ination of factors contributing to health, well-being, and marital satisfaction in older men. Three groups of men were compared: 45 – 54, 55 – 64, and 65 – 74. The following were conclusions related to the issue of sexual desire: (i) sexual interest, responsiveness, and activity was noted even among the oldest men; (ii) increasing age was associated with ED, but not with HSDD or PE (premature ejaculation); (iii) the following frequencies consistently decreased with age: desire for sex, sexual thoughts, maximum time uncomfortable without sex, coitus, and masturbation; and (iv) “… the degree of satisfaction with the men’s own sexual functioning or enjoyment of marital sexuality did not change with age” (36, pp. 41 – 53).
As far as the laboratory is concerned, measuring BAT is the preferred par- ameter for determining hypogonadism, although it is not always available (24). Abnormality is judged by comparing the T level with young adult men (23). “If the testosterone level is below or at the lower limit, it is prudent to confirm the results with a second determination with assessment of LH and … FSH.”
In addition to hormones, many other changes take place in male physiology which contribute to the aging process. One nonsexual example that is cited for the purpose of providing perspective, is the multiple factors which are associated with diminished bone mass and which include: low estradiol (E2), vitamin D deficiency, low GH, low T, poor nutrition, smoking, certain medications, excess alcohol, inactivity, lack of exercise, poor calcium intake, genetic predis- position, and certain illnesses.
The DSM-IV-TR (6) diagnosis of any sexual dysfunction has four requirements: first, diagnostic subtyping must occur (see “Classification” section in this chapter); second, another Axis I diagnosis be excluded (except another sexual dysfunction); third, an existing medical condition could not explain the dysfunc- tion; and fourth, substance abuse also not be present. In the absence of a thorough assessment (history, physical and laboratory exams when appropriate), the clin- ician is actually considering a presenting symptom rather than a diagnosis. The two should not be confused. The distinction is crucial.
Treatment follows diagnostic subtyping (Fig. 1). (A) If HSDD is acquired and generalized, the clinician must make substantial efforts towards finding the explanation(s) for the change. HSDD is sometimes (the frequency appears to be unknown) accompanied by another sexual dysfunction, especially ED, and when both occur together, it may be revealing and useful to find out which came first and to act accordingly. One might envision how a lack of sexual desire can cause erectile problems. However, the opposite is not so clear. The extent to which the presence of ED can result in a generalized lack of sexual desire appears to be entirely unknown. (B) If HSDD is lifelong but situational, a biogenic explanation is unlikely and individual psychotherapy undertaken by a mental health professional seems preferred. (C) If HSDD is acquired but situa- tional, a biogenic explanation is, again, unlikely (with the possibly exception of hyperprolactinemia). In this circumstance, psychotherapy seems indicated but depending on the apparent etiology, could be provided individually or together with a partner. (D) If the history reveals that HSDD has been lifelong and gener- alized, change is unlikely and the clinician should direct therapeutic energy towards helping the person (or, more likely, the couple) to adapt. Kinsey’s admonition seems relevant: “… there is a certain skepticism in the profession of the existence of people who are basically low in capacity to respond. This amounts to asserting that all people are more or less equal in their sexual endow- ments, and ignores the existence of individual variation. No one who knows how remarkably different individuals may be in morphology, in physiological reactions, and in other psychologic capacities, could conceive of erotic capacities (of all things) that were basically uniform throughout a population” (13).
O’Carroll surveyed the psychological and medical literature from 1970 to 1989, searching for controlled treatment studies of HSDD. He found eight such reports, two of which involved only men. (Of the other six, two included both men and women as the “identified patient” and four concerned women as the patients together with their partners) (50). His commentary was critical and reflected sub- stantial discouragement in that he found no controlled studies with a homo- geneous sample in which psychotherapy was the mainstay of treatment and none which included both drug/hormone treatment and psychotherapy.
Nevertheless, some of what does exist in the literature on the psychother- apy of HSDD in men will be reviewed. Heiman et al. considered studies on the treatment of sexual desire disorders in couples (51). None of the studies involved only men; most referred to the treatment of HSDD in women only, or included reports that referred to both men and women as the “identified patient.” Of the three studies that included men with sexual desire difficulties, only one included information concerning diagnostic subtyping (52). The latter investigation reported on a 3-month follow-up of 152 couples in which at least one person had a desire difficulty as part of the presenting complaint. Fifty-eight (38%) of the men had a diagnosis of low sexual desire. Seventeen percent were lifelong and 40% were “global.” Numbers of patients were not given in the report. In com- paring couples in which either the man or the woman presented with a desire dif- ficulty, the authors concluded that initially there was a lower rate of sexual activity when the man was the “identified patient,” that men tended to initiate sexual activity more often, and that men were more likely to have a situational and acquired form of desire difficulty. With a behavioral form of treatment, the authors found at follow-up that significant treatment gains had been made and maintained. In addition, they also claimed that the lifetime/acquired and global/situational distinction “did not predict therapeutic outcome.” This latter statement failed to distinguish between couples in which the man or the woman was the identified patient, unfortunate because it is quite conceivable that the distinction has more meaning for one gender than the other.
The review by Heiman et al. described another study involving a 3-year follow-up of 38 couples treated for sexual dysfunction (53). The group included six men identified as having HSDD with or without another sexual dysfunction diagnosis. Thirty-three percent of all the men had a “notable health problem” (it was unclear how many of the six men with HSDD were in this group). In spite of the fact that a diagnostic subtyping system was adopted, it was inexplic- ably not included in the report. A behavioral form of treatment was used and the results were reported separately for men and women. The authors concluded that “the diagnostically relevant items (that were measured), that is, desire for sexual contact and frequency of sexual contact, clearly demonstrate a lack of sustained success for both men and women.” The Heiman et al. report also included a study by McCarthy of (i) 20 couples in which the results for the men and women were not separately stated and (ii) eight men without partners of whom many reported improvement but the original problems were quite unclear (the example of HSDD given in the report was apparently a result of another sexual dysfunction) (54).
O’Donohue et al. surveyed the sex-related literature on the psychological treatment of male sexual dysfunctions (55). They explicitly excluded studies that relied only on medical intervention. In a clear statement concerning the treat- ment of sexual desire problems, the authors concluded that “no controlled treatment-outcome studies were found for the treatment of … sexual aversion disorder and hypoactive sexual desire disorder … in men.”
Several studies in the O’Donohue review had a mixture of diagnoses and some included men with HSDD. In one such group the results were not reported separately for men and women. Another looked at 40 couples in which the men experienced erectile dysfunction and/or loss of sexual interest, and compared the effectiveness of three treatments: weekly couple counseling, monthly couple counseling, and T (56). Subjects were divided into two groups, with high or low levels of sexual interest. Each group was randomly allocated to (i) testoster- one or placebo therapy and (ii) weekly or monthly counseling. Results indicated no statistically significant group differences in initial clinical ratings and “substantial relapse between the first and second follow-up in the erections ratings and sexual interest ratings.” In addition “the frequency of sexual thoughts at the second follow-up were (statistically) significantly greater in the placebo group.”
O’Carroll’s review found only one study in which a drug was used thera- peutically by itself for HSDD. The investigation concerned the use of bupropion in a nondepressed population (57). The idea of using bupropion therapeutically resulted from the fact that it is a norepinephrine and dopamine reuptake inhibitor and that dopamine is thought to facilitate many aspects of sexual function including desire. As dopamine is linked to sexual stimulation and pleasure, it was thought that bupropion might be helpful for people with HSDD (58).
The study subjects involved 60 patients of which half were men. All of the patients had low desire and 14/25 men had another sexual dysfunction diagnosis as well. Significantly, more (63%) of the bupropion-treated group reported being much or very much improved (vs. 3% of the placebo group) but changes in the frequency of sexual behavior were “much less dramatic and consisted largely of trends .. .”. Unfortunately, results were not reported separately for men and women (an exception being the statement that “more men (86%) than women (44%) showed .. . improvement” with the drug).
O’Carroll’s survey uncovered only one study describing the therapeutic use of a hormone alone. This investigation involved a double-blind crossover comparison of T and placebo in a group of men with normal circulating T levels (59). Ten men complained principally of loss of sexual interest and 10 men complained of erectile failure. The authors found a significant increase in sexual interest pro- duced by T in the first group but qualified this by saying that in only 3/10 of the subjects was it considered to be an “adequate form of treatment,” and in the others, “the changes were either small or did not generalize to the sexual relation- ship.” O’Carroll concluded his review by saying that T “may have a modest role to play in the treatment of some men who present with low sexual interest .. .” but he also cautioned others in the interpretation of the data to remember that this study involved a group of only 10 men (50).
Forms of T (21)
T is weakly soluble in water and is therefore poorly absorbed. In addition, T is rapidly metabolized in the liver. For both reasons, there is limited bioavailability via the oral route and so other methods of delivery have been developed: injec- tions and transdermal (patch, and gel). An exception to comments about oral delivery is testosterone undecanoate (available in Europe and Canada at the time this is written) which is absorbed via the lymphatic system and is therefore only partially inactivated in the liver.
Testosterone enanthate and testosterone cyprionate can be given by injec- tion, usually 150 – 200 mg given every 2 – 3 weeks (amount and frequency depends on blood level monitoring).
Patches deliver 4 – 6 mg/day. Scrotal skin (shaved) is highly permeable but concerns have developed over high levels of DHT and therefore nonscrotal patches have been developed. Gel formulations are applied to nongenital skin. Transdermal methods are advantageous in that one could immediately stop the drug if that seems desirable.
Age-Related Hypogonadal Syndrome (Andropause/ADAM/PADAM)
Not only has the validity of an age-related hypogonadal syndrome in men pro- voked controversy, but it has also raised the issue of whether or not it should be treated with T. In 2002, the National Institute on Aging and the National Cancer Institute asked the Institute of Medicine (IOM) to conduct an independent assessment of the potential benefits and adverse health effects of testosterone therapy in older men and to offer recommendations. The result was the report entitled: “Testosterone and Aging” (21).
Treatment with T is approved for the care of clearly established male hypogonadism—at any age. However, there have been few studies (especially randomized, double-blind, and placebo-controlled) on the use of T in healthy middle-aged or older men who may have a T level in the low range of a young adult but may also have one or more symptoms that are common both to hypogonadism and aging. The IOM report summarized their review of studies on the use of T in older men by cautioning that although finding 31 placebo- controlled trials, the largest sample size involved 108 subjects, the duration of treatment in 25 of the trials was 6 months or less, and only one lasted more than 1 year. In what might be interpreted as understatement, the report concluded that “… assessments of risks and benefits have been limited, and uncertainties remain about the value of this therapy for older men” (21; pp. 1 – 2).
One can do little better than quote from some the comments and judge- ments in the IOM report: “Viewed by some as an anti-aging tonic, the growth in testosterone’s reputation and increased use by men of all ages in the United States has outpaced the scientific evidence about its potential benefits and risks” (p. 11). “Experience with the use of postmenopausal hormone therapy in women and the growing body of scientific evidence about its risks and potential benefits provides an apt and timely example of the need for sustained analysis of short- and long-term effects of new treatments and the caution that must be exer- cised in widely prescribing drugs as preventive measures. In the meantime, clin- icians are searching for therapies, and an enthusiastic and perhaps overly optimistic citizenry is eager to not only treat diseases associated with aging but also possibly delay the timing of their initial onset” (p. 163).
Testosterone Replacement Therapy (TRT): General and
Adverse Effects (24)
Sexual: (a) In hypogonadal men: Primary effect appears to be central and on sexual desire (mediated by markedly increased fantasy), rather than peripheral on the genitalia; sleep-related erections are androgen-dependent as is the rigidity of those erections; androgens have no effect on visual erotic stimuli. (b) On eugonadal men: “It is assumed that (normal) men have plasma androgens at con- centrations substantially higher than the threshold levels required for behavioral activation”; desire increased without change in sexual behavior (60).
Prostate: Increase in prostate size and in prostate-specific antigen (PSA), but the prostate remains within normal size for eugonadal men and the PSA within normal levels. “The possibility cannot be excluded that promotion of pre- cursor lesions is stimulated by androgens; therefore, androgen substitution should not lead no [sic] superphysiological [sic] plasma levels of androgenic steroids.” This warning must make clinicians especially vigilant in view of the fact that incidental prostate cancer is found in 10% of men undergoing surgery for an enlarged prostate. Some believe that a biopsy should be done before initiation of hormonal treatment.
Hematopoiesis: Stimulation of renal production of erythropoietin (by both T and DHT); evidence for a direct effect of androgens on erythropoietic
stem cells; androgen receptors have been found in cultured erythroblasts. However, treatment with T does not always lead to problems with polycythemia.
Sleep apnea: Exacerbation of pre-existing sleep apnea; special attention should be given to men who are overweight, heavy smokers, or who have chronic obstructive lung disease.
Gynecomastia: Especially in men with liver or kidney disease.
Body composition: Decrease in body fat; increase in lean body mass;
and change in some aspects of muscle strength.
Bone: Increase in bone density and slowing of bone turnover.
Mood and cognition: Improvement in spatial cognition; improvement in sense of well-being.
Body fluid and glucose metabolism: Fluid retention (resulting in worsening hypertension); peripheral edema; congestive heart failure; decrease in fasting blood glucose; decrease in insulin resistance.
Skin: Change in regulation of sebaceous glands and hair growth.
Depending on the cause, hyperprolactinemia can be treated medically or surgically.
When the etiology is a prolactin-secreting tumor of the pituitary gland (pro- lactinoma), then surgery becomes an option. The sooner such a diagnosis is made the better since 40% of patients already have visual field defects at the time of presentation.
Most commonly, hyperprolactinemia is treated medically by using dopa-mine D2 agonists such as bromocriptine initiated at 2.5 mg/day and titrated up to 25 mg/day, or cabergoline, a longer acting dopamine agonist, starting at 2.5 mg twice a week and increasing to 0.5 mg twice/week (22; p. 34 – 35). As psychosis is a side effect of bromocriptine it should be used with caution.
Drug-Induced Diminished Desire
. Hyperprolactinemia: (described earlier)
. Strategies for antidepressants (22; p. 60): (i) decrease dosage, (ii) drug holiday, (iii) small dose of neostigmine 7.5 – 15 mg before intercourse, and (iv) add dopaminergic agent [e.g., bupropion 150 mg/day or more; dextroamphetamine, methylphenidate, permoline (starting with low dose, for example, 5 mg of methylphenidate and titrate up)].
. Cancer chemotherapy: Androgen replacement therapy is often suggested to men who have received high dose chemotherapy associ- ated with bone marrow transplantation.
SUMMARY AND CONCLUSIONS
Some may see it as a truism that men and women are sexually different, but in the latter half of the 20th century there has been a strong effort to view the two as functionally symmetrical. In spite of this attempt at equation, evidence about just how men and women differ, especially in the crucial area of sexual desire, is rapidly accumulating. Although doubtlessly unintentional, investigations of sexual desire in women have shed light on the same in men. These observations have insinuated that the pattern of sexual desire resulting in arousal is more true of men than women (where desire might follow arousal), and that sexual desire tends to be quantitatively greater in men.
According to several different studies, at any one time 16% of men experi- ence HSDD. However, sexual desire manifests in different ways (both psycholo- gically and behaviorally), and it is far from clear just who is included in this 16%. Does it represent, for example, men who have sexual thoughts but do not act on them? Men who act on some occasions but not others (acquired and situational)? Men who had sexual thoughts and feelings in the past but not nowadays (acquired and generalized)? Men who do not have those feelings now and never have thought much about sexual issues (lifelong and generalized)? The tendency of sexual desire in men to decline as they become older has been repeatedly demon- strated. But does this observation mean that an elderly man who experiences diminished sexual desire has HSDD and is part of the 16% (men who are some- times referred to as having “andropause,” “ADAM” or “PADAM”? Or, conver- sely, should we look at the age-related decline not as pathological, but rather as a “normal” part of the process of becoming older? And who decides the answer? Is this a medical decision made by health professionals or one which is social? Lots of questions and few answers. The “bottom line” is that the definition of HSDD in men in most studies is quite unclear, so one might fairly ask (at least rhetorically): just what are the boundaries surrounding the diagnosis?
Apart from the issue of diagnostic borders, the assessment of HSDD in men is not complicated and involves a few questions in the history about sexual thoughts, fantasies, activities with a partner or oneself, a consideration of health status, and conducting a few laboratory tests. Those procedures will help in the process of subtyping, which, in turn, is essential for determining etiol- ogy and treatment.
Each of the subtypes of HSDD has many possible origins. For example, if a man finds that he is completely absorbed sexually at the beginning of a new relationship and not otherwise, or only when watching a computer screen display- ing engaging women without clothes, then obviously his sexual desire is quite intact but is highly focussed. In this instance, biomedical speculation about the etiology will not (with the possibly exception of hyperprolactinemia) be fruitful and does not make clinical sense. Thinking in psychosocial ways about etiology and treatment in such an instance will be more productive and, on the basis of clini- cal experience, intrapersonal issues involving the capacity for intimacy loom large.
If, on the other hand, the man has desire difficulties of relatively recent origin which extend to all circumstances when he would be expected to react with sexual feelings, then a clinician might indeed think about biomedical matters. Medical and psychiatric disorders, or medications used in treatment, appear to be a frequent cause of acquired HSDD. If the man is ostensibly healthy, considering subtle problems like hormone aberrations might prove helpful. Two hormones in particular greatly influence sexual desire, namely, tes- tosterone and prolactin, and both must be scrutinized if the problem is generalized.
Published information on the treatment of HSDD in men who do not have any obvious explanation for their difficulties, leaves clinicians with little gui- dance. First, diagnostic subtyping is virtually nonexistent. Second, there are no controlled studies on a homogeneous sample of men in which psychotherapy was the mainstay of treatment. As well, a review of the use of couple therapy resulted in pessimistic conclusions. Third, only one placebo-controlled drug study (bupropion in a nondepressed mixed population of men and women) has taken place but fortunately suggested improvement. Fourth, only one study of the use of a hormone (testosterone) alone has occurred but included a mere 10 patients, a fact which even one of the authors decried.
HSDD in men can be an agonizing condition, especially when sexual desire is actually present but is not expressed in a way that involves the patient’s partner. The reproductive consequences can be severe. To suggest that more research is needed into this disorder would be an understatement. All aspects of HSDD in men need to be carefully examined, starting with as basic an issue as trying to clarify what is encompassed within the definition.