'Off-Label' Drug Use in Sexual Medicine Treatment

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'Off-Label' Drug Use in Sexual Medicine Treatment

B Fallon Int J Impot Res. 2008;20(2):127-134. ©2008 Nature Publishing Group

Posted 04/10/2008

Abstract and Introduction

Abstract

Phosphodiesterase type 5 inhibitors are the only drugs approved for a specific sexual function disorder. All other drugs used in the treatment of sexual disorders are used 'off-label.' This paper reviews the use of drugs in the treatment of premature ejaculation, Peyronie's disease and female hypoactive sexual desire disorder (HSDD). While the treatment of premature ejaculation is quite well documented and supported by evidence of good quality in the medical literature, there is little evidence for the use of the variety of medications in use for the treatment of Peyronie's disease. In particular, the use of verapamil is not supported by any double-blind studies whatsoever. The use of testosterone patch for treatment of HSDD in postmenopausal women is well documented, but not in premenopausal women.

Introduction

'Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product's use and effects'.[1] Thus, the US FDA (United States Food and Drug Administration) allows the off-label use of medications in the practice of medicine without Institutional Review Board review.

Off-label use often means that tolerability, safety and efficacy data are not available for that use. The classes of drugs most commonly used off-label are anticonvulsants, antipsychotics, antihistamines, antiasthmatics and cardiovascular agents. According to one study, approximately 21% of all prescriptions are written for off-label indications in office practice, and approximately 73% of those off-label uses have little or no scientific support.[2] In that study, the only drug mentioned that was relatively commonly used in Urology was amoxicillin. Twenty-five percent of amoxicillin usage was off-label, with half of those prescriptions having 'little or no scientific support'. The overall relative risk of antimicrobials being used off-label was 1.96, using analgesics as the referent. The great majority of drug use in pediatric practice is off-label, as therapeutic trials are rarely conducted in pediatric patients. Likewise, drug treatment in oncology and HIV treatment is commonly off-label.

Insurers frequently will base reimbursement for off-label use on whether that use is mentioned in a standard drug compendium such as the American Hospital Formulary Service-Drug Information (AHFS-DI), or the United States Pharmacopeia-Drug Information (USP-DI). Such mentions give 'respectability' and acceptance to that use, indicating that it is within the standard of care for that disease, and consistent with community practice,[3] usually based on accumulating evidence of efficacy in the literature. At least 36 states now require insurers to provide coverage for off-label use if the drug is recognized as appropriate for such use in one of the major drug compendia, in relevant peer-reviewed literature, or by the Secretary of Health and Human Services.[4] Drug manufacturers will not usually try to get FDA approval for off-label uses of their products because of the time and expense involved, and may be subject to legal action by the FDA if they market products for off-label uses.[5]

Drugs Used in Treating Sexual Dysfunction

Some of the drugs that are commonly used in the treatment of sexual dysfunctions are listed in Table 1 . Of these, phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are FDA-approved for treatment of male erectile dysfunction, and testosterone is approved for the treatment of delayed puberty and hypogonadism in men. All other drug usage in the treatment of sexual dysfunctions is off-label, some with good evidence of efficacy, and some without. This paper briefly reviews some of the off-label treatments of premature ejaculation (PE) and Peyronie's disease (PD), and also the off-label use of testosterone in female hypoactive sexual desire disorder (HSDD).

Premature Ejaculation

All medical treatment for PE is off-label. Drugs used extensively in treatment are principally the selective serotonin reuptake inhibitors (SSRIs), PDE5 inhibitors and clomipramine, a tricyclic antidepressant. Also commonly used are local anesthetic creams, sprays and gels.

Antidepressants

Serotonin and 5-hydroxytryptamine are involved in the central control of ejaculation. Rat studies have found that SSRIs block presynaptic membrane 5-hydroxytryptamine transporters, resulting in delayed ejaculation.[6] Increased serotonergic stimulation resulting from SSRIs or clomipramine results in the prominent side effect of delayed ejaculation noted by patients taking these drugs for treatment of depression. The clinical effects of SSRIs in treating PE were first reported in 1994, when eight patients were treated with paroxetine, and compared to nine treated with placebo. The paroxetine dose was 20 mg day-1 for week 1 and 40 mg day-1 for the next 5 weeks of the trial. Intravaginal ejaculatory latency time (IELT) was felt by patients and partners to be longer with paroxetine.[7] A meta-analysis of 35 SSRI and clomipramine daily dose studies found that only eight studies were conducted according to evidence-based medicine standards.[8] In these eight studies, there was a placebo effect of a 1.4-fold increase in IELT, while paroxetine averaged an 8.8-fold increase in IELT, and clomipramine, sertraline and fluoxetine all increased IELT by approximately four-fold. These drugs appear to be active both for lifelong PE and for acquired PE. Duloxetine, a dual serotonin and epinephrine reuptake inhibitor has also been found to produce approximately a four-fold increase in IELT in a 4-week randomized trial.[9]

Onset of activity with antidepressants used on a daily basis is within 1—2 weeks. Treatment may be continued for a period of several months and a trial of discontinuation may be done. Men who have had acquired PE may permanently maintain their improvement. Unfortunately, in cases of lifelong PE, relapse occurs within 6 months in at least 66% of patients.[10] Treatment can, however, be continued for years, although tachyphylaxis may occur.[8] Typical doses of the antidepressants used in PE treatment are shown in Table 2 .

Side effects of SSRIs. All have similar side effects, with nausea, drowsiness, perspiration and erectile dysfunction, with anejaculation being common on initiating treatment, but lessening within several weeks. Other, less-frequent side effects include abnormal bleeding, hypoglycemia, hyponatremia and movement disorders. There is also a well-recognized SSRI discontinuation syndrome, which may begin within 1—3 days of stopping the drug and lasting for about 7—10 days. The symptoms may consist of nausea, dizziness, headache, anxiety, insomnia and gait instability.

On-Demand SSRI Treatment

Trials have been conducted of SSRIs taken 1—2 h prior to intercourse. Typically, the IELT does not seem to have increased as much as with daily treatment. Also, side effects such as nausea, loose stools and drowsiness may interfere with the pleasure of intercourse. These side effects tend to improve with daily usage.

A new SSRI, dapoxetine, was developed specifically for use as on-demand treatment for PE, and in one study seemed very promising in doses of 30 and 60 mg. IELT increased 2.8 and 3.6 times over baseline respectively, while placebo increased IELT 1.8 times.[11] Patient self-ratings of control over ejaculation increased from 2.8% at baseline to 52 and 58% respectively with the 30 and 60 mg doses. The drug's half-life is short and the absorption rapid. Peak serum concentration occurs in about 1 h and serum levels at 24 h are less than 5% of peak levels. Typical SSRI side effects occur—nausea, headache, diarrhea and dizziness, with occasional syncope. Sexual side effects are uncommon as noted in a 9-month open label study, which found an incidence of only 2.6% in 1774 patients with a 60 mg dose.[12] Dapoxetine, however, did not receive the expected FDA approval, and is not in general use.

Tramadol HCl is a centrally acting opioid analgesic that exerts its effect through the inhibition of norepinephrine and serotonin reuptake. A recent investigation of its use in PE found that it is effective in a dose of 25 mg.[13] Taken 1—2 h before sexual activity, it produced an increase in IELT from a mean of 1.17 min to a mean of 7.37 min (stopwatch observations). Placebo produced a mean IELT of 2.01 min in that trial.

Topical Anesthetic Ointments

Local anesthetics in gel or cream form have historically been used to reduce penile sensitivity and delay ejaculation. They are inexpensive, but may lead to erectile difficulties secondary to glans numbness, and may also reduce vaginal sensation in the partner if a condom is not used. In one double-blind study of 42 patients using a lidocaine/prilocaine cream, IELT increased from 1.5 min in the treatment group to 8.5 min, while in the placebo group the increase was from 1.67 to 1.95 min. Sexual satisfaction scores did not change significantly in either group.[14] Another double-blind, randomized study of a lidocaine/prilocaine spray in 55 patients found an increase in IELT from 1.9 to 4.9 min in the treatment group, compared to an increase from 0.9 to 1.6 min in the control group.[15] There were also significant improvements in sexual satisfaction scores with the spray. Another study of a lidocaine/prilocaine cream found that EMLA cream produced a 65% improvement or cure rate in PE patients.[16] Unfortunately, the patient numbers were small, IELT was not documented and patient self-assessments were the evaluating tools. Also of note is that placebo cream alone produced a 40% rate of cure or improvement.

None of the studies of topical agents are large and although these agents are frequently used, convincing data about their effectiveness are not available, and patients do not often continue to use them long-term.

PDE5 Inhibitors

There are several studies in the literature regarding the use of PDE5 inhibitors for PE. They suggest that there may be decreased contractile response of the seminal vesicles, vas deferens and urethra due to smooth muscle relaxation. Many of these studies include the concomitant use of antidepressants, local anesthetics or behavioral therapy. For example, in the study of EMLA cream noted above, one of the study groups received sildenafil only, and another received sildenafil plus EMLA cream. The sildenafil groups did not have any statistically significant improvements over the EMLA only group.[16] Another randomized, double-blind crossover study of 31 patients found that sildenafil was superior to SSRIs and the squeeze technique. IELT was measured with a stopwatch, and improved from 1 min at baseline to 3 or 4 min with SSRIs, and to 15 min with sildenafil.[17] Sexual satisfaction scores were higher and anxiety scores lower. Another study noted that although sildenafil did not improve IELT, it did produce increased sexual satisfaction, and increased confidence and decreased post-ejaculatory latency time.[18] A recent review of the literature regarding use of PDE5 inhibitors in PE found 14 such studies between 2001 and 2006.[19] There was large variation in methodology, differences in definition of PE, small numbers of patients, poorly designed studies and inclusion of both acquired and lifelong PE patients. As a result, a meta-analysis could not be performed, and it was felt that the findings and conclusion of 13 of the 14 studies should be regarded as unreliable. Some studies seem to provide evidence of efficacy in men who have coexistent PE and erectile dysfunction, possibly due to increased confidence in the quality of erection producing a lesser anxiety regarding achieving orgasm and ejaculation.

Peyronie's Disease

Peyronie's disease was historically regarded as self-resolving until 1990, when it was noted in a series of 97 patients who had the disease for periods ranging from 3 months to 8 years that only 13% felt there was spontaneous improvement, 47% noted no change and 40% felt that there was progression during the observation period.[20] It is thought to affect as many as 8.9% of men. Numerous oral, intralesional and transdermal therapies are in use, most of which have an anti-inflammatory action, and none of which are approved by the FDA for the treatment of PD.

Oral Medications

Oral therapies that are sometimes used in the treatment of PD include vitamin E, colchicine, tamoxifen, carnitine and aminobenzoate (Potaba). There are no substantial, randomized, double-blind studies of any of these drugs, which demonstrate convincing effectiveness greater than placebo in the pain or curvature of PD. Nevertheless, vitamin E and Potaba are still frequently used, probably more as a method of mollifying patient demands than with hope of real results. Vitamin E is harmless and inexpensive, and fills a void for the physician who does not have the courage to tell patients that there is no good oral treatment. Potaba has been studied in a multicenter randomized, double-blind study, in a dose of 12 g, daily for 12 months[21] (six large tablets four times daily!). Response rate was 74%, compared to 50% for placebo, using end points of reduction in plaque size and/or penile curvature reduction of 30º. Preexistent curvature was not reduced, but new curvature was not as severe as in the Potaba group. Pain response was no different in either the Potaba or placebo group. Side effects are mild, mostly nausea and anorexia. In clinical practice, many physicians use Potaba, but in private conversation, few have real faith in its benefits. The large number of tablets, the four times daily dosage, and the price of approximately $400 per month surely induce a strong placebo effect.

Transdermal Therapy

Verapamil is a calcium-channel blocker, which increases collagenase activity and inhibits fibroblast activity. Topical treatments of the PD penis with verapamil and cortisone have been reported to produce improvements in pain, curvature and progression. However, much doubt was cast upon these results when it was noted that verapamil was not found in tunica albuginea biopsies of eight patients undergoing penile prosthesis operations who had been pretreated with topical verapamil.[22] That study is frequently quoted to show that there is no scientific basis for the use of verapamil gel; however, the verapamil gel was only applied to the shaft of the penis the night before and the morning of surgery, and was washed off prior to surgery. The study is therefore meaningless considering that the recommended use of the gel is long-term.

Iontophoresis is the use of small amounts of electric current to assist in transdermal application of medications. It has been used in PD and found to produce detectable verapamil levels in 10 of 14 tunica albuginea samples taken from patients undergoing surgery.[23] A recent study of verapamil and dexamethasone applied electromotively found a decrease in plaque volume (from 824 to 348 mm3) and a decrease in curvature from 43 to 21º, with no improvements in the placebo arm.[24] Unfortunately, this treatment involved four 20-min sessions per week for 6 weeks. Cost was not mentioned, but with lack of other supporting data in the literature, it is not likely that this will become a common form of treatment.

A recent publication may have resurrected the debate regarding topical verapamil directly applied to the shaft of the penis.[25] The study involved 57 patients, of whom 20 were randomized to a 15% topical verapamil solution, and 20 to placebo. After 3 months of twice-daily applications, curvature improved in 78% of the verapamil patients compared to 29% of the controls. Pain resolved in 87 and 37%, respectively. Continuation of treatment for 9 months produced further improvements, especially in plaque size. The authors claim that results are superior to intralesional therapy, but the patient numbers are obviously very small, and perhaps publication could have been delayed until larger numbers were accrued.

Intralesional Therapy

Several drugs have been and are used by direct injection into the Peyronie's penile plaque. This obviously produces higher local concentration of medication with expectations of reduced systemic toxicity.

Corticosteroids. Multiple studies of corticosteroid injection have been published, but this treatment has never achieved broad use because of side effects, including tissue atrophy. One study claims elimination of pain, curvature and plaque in 97, 32 and 31%, respectively, with a combination of betamethasone and hyaluronidase.[26] Best results were obtained in patients whose disease was present less than 12 months and with plaques of less than 2 cm.

Collagenase. Purified clostridial collagenase has been used in a prospective, randomized double-blind study with a crossover retreatment arm. Forty-nine patients were enrolled and increasing doses were used according to the severity of curvature.[27] Only one injection was administered intralesionally. Three patients with curvature less than 30º responded well, as did 4 of 11 patients with 30—60º curvature. Only one of eight patients with curve greater than 60º responded. This paper is frequently quoted, but has not been followed up in the literature. Results were actually not very good, and numbers were inadequate.

Interferons. The rationale for using interferons (IFNs) to treat PD is based on studies demonstrating that human recombinant IFN-α and -β inhibited fibroblast and collagen production and increased collagenase production in the presence of cultured fibroblasts from Peyronie's plaques.[28] Intralesional IFN treatment seems to be increasing in popularity, mainly because toxicity is low, patients prefer to avoid surgery and perhaps because the number of office visits required to complete a course of treatment is quite profitable for the physician.

Clinical experience has not been encouraging. One study of 30 patients given three injections of 3 million units of IFN-α-2b found clinical improvement in one patient,[29] stability in 26 and worsening in the remaining three. Side effects were common. Seventy-four of 90 injections resulted in fever >38 ºC. Another study found good pain relief in 10 patients receiving nine injections of 1.5 million units over a 3-week period.[30] Six of those patients had improvement in angulation, averaging 20º. Another study found no statistically significant changes in objective or subjective parameters in patients treated with 12 weekly injections of 5 million units of IFN-α-2b, supplemented with oral vitamin E.[31] By far, the most optimistic study is a multicenter study of 53 patients treated with placebo and 50 treated with six injections at 2-week intervals of 5 million units of IFN-α-2b. Curvature improved from 50 to 36º in the IFN group, and from 51 to 46º in the saline group.[32] Plaque size decreased by 54 and 20% respectively, and pain resolved in 67 and 28% in the IFN and placebo groups. IIEF scores were not significantly different between the groups, which may be the most significant result. Overall, these results are not impressive.

Verapamil. The first clinical report of intralesional verapamil therapy in PD recounted injections every 2 weeks in 14 patients for 6 months.[33] Two patients dropped out during treatment. Ten milligrams of verapamil in 10 ml were injected using a 25 G needle and 100—150 plaque punctures each time. Ten of 10 patients had pain resolution, 9 of 9 bottleneck deformities resolved and 5 of 12 had curvature improvement. Four patients had surgery later.

The same group later reported experience with 156 men. No placebo comparison was available as 'placebo treatment could cause harm and there is no existing standard of care to use for comparison'.[34] The mean curvature pretreatment was apparently less than 32º. The mean post-treatment curvature is difficult to discern from the study, but 62% of patients reported an improvement of a mean of 31º, while 30% found no change. Eleven percent (31 of 37%) reported improved distal erection. Fifty-nine percent (92 of 156) of patients claimed improved sexual function. Pain relief was reported by over 90% of patients during the 6-month course of therapy. There were few complications in this report.

A randomized study of seven patients treated with verapamil versus seven in a control saline group found no significant change in curve, while plaque volume decreased by 57 and 28% in the verapamil and saline groups respectively.[35] Injections were weekly for 6 months. It was noted that this treatment is unsuitable for patients with greater than 30º of curvature, or who did not respond within 3 months. A recent study of 94 patients treated with six injections of 10 mg verapamil found improvement in curvature in 18%, with no change in 60% and worsening in 22%. Average curve was 50º at baseline and 47º after treatment. The title of this study 'Intralesional Verapamil Prevents the Progression of Peyronie's Disease' is not justifiable, as there was no control group.[36] Perhaps the authors just did not wish to flatly state that verapamil does not work.

A recent literature review of intralesional injection studies in PD found a total of 19 published studies, including four verapamil studies.[37] Sixteen of these were level 4 according to the Oxford Center for Evidence—Based Medicine criteria (case series—level 5 is the lowest, expert opinion). Three of the four verapamil reports were level 4, and the fourth study, noted above, had only 14 patients.

Androgens in Hypoactive Sexual Desire Disorder in Women

Sexual dysfunction is common in women, with one study reporting a 43% prevalence.[38] This was based on data from the National Health and Social Life Survey of 1749 women aged 18—59 years. Thirty-two percent of those between 18 and 39 complained of lack of interest in sex, while 26% of those between 49 and 59 had that complaint. It was less common in married women (29%) than never married or divorced (35%). Greater degrees of education correlated with greater interest in sex, as 42% of those with less than high school had low interest and only 24% of college graduates had the same complaint. A consensus conference in 1999 defined four categories of female sexual dysfunction, and HSDD was defined as 'the persistent or recurrent deficiency (or absence) of sexual fantasies/thoughts, and/or desire for or receptivity to sexual activity, which causes personal distress'.[39]

Androgen Therapy

Androgen insufficiency has been identified as one of the many factors inducing HSDD. Symptoms of androgen insufficiency include diminished sense of well-being, fatigue, decreased libido and sexual pleasure, and may be accompanied by bone loss, and decreased strength and memory.[40] Such symptoms should be accompanied by diminished serum androgen levels in the presence of normal estrogen before androgen therapy is considered. Androgen levels in premenopausal women without sexual complaints were found to decrease from age 20 to 49 years. Dehydroepiandrosterone-sulfate decreased from 195 to 140 μg dl-1, total testosterone from 51 to 34 ng dl-1 and free testosterone from 1.5 to 1.0 pg ml-1. There was no change in sex hormone-binding globulin.[41] Another study of 1423 women between 18 and 75 years old found similar decreases in premenopausal women, with no further decreases post-menopausally.[42] Several studies have evaluated androgen levels in women with HSDD, and these provide no definitive evidence of lower levels in HSDD compared to normal women. Nevertheless, androgen therapy is prescribed extensively, and there is significant evidence in the literature of its efficacy, at least in post-menopausal patients. Table 3 summarizes some of these reports.

All the studies quoted above were randomized, placebo-controlled, double-blind studies. Most used 300 μg testosterone patches applied daily. None reported any severe side effects. All noted significantly increased serum levels of total testosterone, free testosterone and bioavailable testosterone. Estradiol and estrone levels, when checked, did not change significantly. Most of these trials were 24 weeks in duration, so long-term data regarding the safety and efficacy of androgen therapy in HSDD are lacking. Thus, the FDA has not approved testosterone patch treatment for women at this time. Prior to development of the transdermal patch, several studies showed benefit in women with HSDD from injectable or oral testosterone preparations, but these produced oscillating and supraphysiological serum levels of androgens. The transdermal system seems to produce good results, with no significant masculinization effects.

Of note, however, is that all the above studies are in postmenopausal women, and there are no randomized, placebo-controlled studies in premenopausal women with HSDD. The Endocrine Society appointed a Task Force to produce practice guidelines for the use of androgen therapy in women. That Task Force recommended against making a diagnosis of androgen deficiency in women pending proper definition of a deficiency syndrome, based on reliable normative data on androgen levels across the life span. They also recommended against the generalized use of testosterone by women, because of inadequate indications and lack of long-term data.[47]

Conclusion

Off-label use of drugs is common in treating sexual disorders in men and women. It is reasonable to recommend the routine use of a particular treatment if there is high-level evidence of efficacy and safety. In general, for medical problems that are not life threatening, or do not seriously impact health, the quality of the evidence should be high-level 1 or 2, using the Oxford Center for Evidence-Based Medicine criteria. Of the conditions and medications discussed above, the use of SSRIs (with daily dosing) in PE seems to have a reasonable evidence-based justification. None of the treatments for PD has evidence-based justification, as there are essentially no randomized controlled trials. Androgen therapy in female postmenopausal HSDD appears to have a sound basis, and may achieve FDA approval at some point. Trials of androgen in premenopausal women are inadequate.

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Table 1. Drugs Used in Treating Sexual Dysfunctions and Their Approved and Off-Label Uses

Drug

FDA approved

Indication

Off-label use

USP-DI mention

Evidence-based?

SSRIs

Yes

Antidepressants

PE

Yes

Yes

Clomipramine

Yes

Obsessive-compulsive

PE

Yes

Yes

Local anesthetics

Yes

Topical anesthesia

PE

Yes

Questionable

Tramadol

Yes

Pain relief

PE

No

Questionable

PDE5 inhibitors

Yes

Male ED

PE

No

No

Verapamil

Yes

Antiarrythmic; angina

Peyronie's disease

No

No

Vitamin E

No

Nutrition supplement.

Peyronie's disease

No

No

Corticosteroids

Yes

Anti-inflammatory

Peyronie's disease

No

Very questionable

Paraaminobenzoate

Yes

Anti-inflammatory

Peyronie's disease

Yes

Very questionable

Interferon-α-2a

Yes

Immunologic

Peyronie's disease

No

No

Collagenase

Yes

Skin debridement

Peyronie's disease

No

No

Phenylephrine

Yes

Decongestant

Priapism

Yes

Yes

Epinephrine

Yes

Bronchodilator

Priapism

Yes

Questionable

Papaverine

Yes

Smooth muscle spasm

Male ED

Yes

Yes

Phentolamine

Yes

Acute hypertension

Male ED

Yes

Yes

Trimix

No

Male ED

Yes

Yes

Bimix

No

Male ED

Yes

Yes

Yohimbine

No

Mydriasis

Male ED

Yes

No

Testosterone

Yes

Male hypogonadism

Male ED

Yes

Yes

Female sex dysfunction

No

Yes

ED = erectile dysfunction; PDE5 = phosphodiesterase type 5; PE = premature ejaculation; SSRI = selective serotonin reuptake inhibitor; USP-DI = United States Pharmacopeia-Drug Information

Table 2. Antidepressant Dose in Premature Ejaculation.

Drug

Usual daily dose (mg)

Paroxetine

20—40

Sertraline

50—100

Fluoxetine

5—40

Citalopram

5—20

Clomipramine

20—50

Duloxetine

20—50

Table 3. Androgen Therapy in HSDD

Reference

Treatment

No.of patients

Result

Side effects

[43]

Est. vs Est.+Test.

218

Increased androgen. Increased sexual interest and desire

None severe. Headache (9%) hot flushes (6%), acne (6%). Same for both groups

[44]

Est. vs Placebo vs Test.

75

↑Androgen. ↑Frequency sex. ↑Pleasure. ↑Desire (NS). ↑Well-being

Acne, facial hair. Lipids, hematocrit, liver function all stable

[45]

Placebo vs Test.

447

↑Androgen, more with ↑ dose. Estrogen levels unchanged. Desire, arousal, pleasure, orgasm and frequency all ↑

12% withdrew; same for placebo. Acne, headache, hirsutism, breast pain, patch reaction, all same for placebo

[46]

Placebo vs Test.

77

Androgens ↑. Desire, arousal, orgasm, self-image and frequency all ↑. Androgen levels correlated with all improvements

0 serious. Hirsutism, acne. Patch reaction (worse with placebo); 18 patients withdrew (10 placebo, 8 test)

Est. = estrogen; HSDD = hypoactive sexual desire disorder; Test. = testosterone

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