FT-01423/June 2011

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Testosterone Overview

Wasim Deeb,MD

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Agenda

• Insights and challenges in the diagnosis and management of low testosterone (low T)

• Controversial Issues of (testosterone) • Treatment Options

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FT-01423/June 2011

Insights and Challenges in the Diagnosis and Management of Low

Testosterone (Low T)

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Testosterone Regulation: Hypothalamic-Pituitary-Gonadal (HPG) Axis

Testosterone

Spermatozoa

LH

FSH

1. Gonadotropin-releasing hormone (GnRH) secreted from the hypothalamus stimulates anterior pituitary

2. Anterior pituitary releases follicle stimulating hormone (FSH) and luteinizing hormone (LH)

3. LH stimulates Leydig cells in the testes to produce testosterone

4. FSH stimulates Sertoli cells in the testes to produce spermatozoa

Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696.

(-)

Hypothalamus

Pituitary gland

Hypothalamus

Posterior pituitary

Anterior pituitary

Testes

(-)

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Testosterone Distribution in the Body

SHBG, sex hormone binding globulin. Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6):682-696.

SHBG-bound Albumin-bound Free in Blood 1%-2% 40%-50% 50%-60%

Bioavailable Testosterone

Total Testosterone

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Hypogonadism: Definition

Hypogonadism in men is a clinical syndrome that results

from failure of the testis to produce physiological levels of

testosterone (androgen deficiency) and a normal number of

spermatozoa due to disruption of one or more levels of the

hypothalamic-pituitary-testicular axis.

Bhasin S et al. J Clin Endocrinol Metab. 2010;95:2536-2559.

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Types of Hypogonadism Include

Primary (congenital or acquired)

Hypogonadotropic (congenital or acquired)

Testicular failure due to conditions such as • Cryptorchidism • Bilateral torsion • Orchitis • Vanishing testis syndrome • Orchiectomy • Klinefelter syndrome • Chemotherapy • Toxic damage from alcohol, heavy metals

• Idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency

• Pituitary-hypothalamic injury from tumors, trauma, or radiation

• These men usually have – Low serum testosterone concentrations – Gonadotropins (FSH and LH) above the

normal range

• These men have – Low serum testosterone concentrations – Gonadotropins in the normal

or low range

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Symptoms Associated With Male Hypogonadism Include

Psychological

• Depressed mood • Decreased

sexual desire • Regression of

secondary sexual characteristics

• Erectile dysfunction

• Loss of energy and fatigue

• Osteoporosis

Physical

Sexual

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In the Hypogonadism in Males (HIM) Study, the Prevalence of Hypogonadism Was

Estimated to Be Nearly 40%

Mulligan T et al. Int J Clin Pract. 2006;60(7):762-769.

39% 34%

40% 40% 46%

50%

0.0

10.0

20.0

30.0

40.0

50.0

60.0

Total (45+)

45–54 55–64 65–74 75–84 85+ Age Range, years

Prev

alen

ce o

f Hyp

ogon

adis

m, %

• The HIM study estimated the prevalence of hypogonadism (< 300 ng/dL) in 2165 men over 45 presenting to 95 primary care practices in the United States

Reprinted from Int J Clin Pract, 60, Mulligan T, Prevalence of hypogonadism in males aged at least 45 years: the HIM study, 762-769, 2006, with permission of John Wiley & Sons, Inc.

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Discussion

• <10% • 25%-40%

Mulligan T et al. Int J Clin Pract. 2006;60(7):762-769.

Only 9% of the men with low T in the HIM Study were treated with TRT

Of the men believed to have low T in the HIM study, what % were being treated with testosterone replacement therapy (TRT)?

• 50%-70% • >90%

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Why Might Low T Be Undertreated?

• Some hypothesized reasons5

– Clinical symptoms may not be obvious – Lack of time for physician-patient interaction21 – Lack of agreement on laboratory cutoff values – Difficulty in assessing patient-specific factors

(eg, illness, medications, stress) – Serum testosterone test variability due to time of day

or season – Multiple guidelines and treatment algorithms – Higher priority given to other comorbid diseases 5. Miner M et al. Postgrad Med. 2008;120(3):130-153.

21. Tai-Seale M et al. Health Serv Res. 2007;42:1871-1894.

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Common Comorbidities Among Hypogonadal Men in the HIM study

Mulligan T et al. Int J Clin Pract. 2006;60(7):762-769.

• A history of hypertension, hyperlipidemia, diabetes, and obesity were each reported significantly more often by hypogonadal men compared with eugonadal men in the HIM study

p<0.001 p<0.001

p<0.001 p<0.001

65.4 60.5

30.9 32.3

51.1 50.5

17.9 17

Patie

nts,

%

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Endocrine Society Guidelines for Screening for Low T

• Screening for low T is not recommended in all patients

Bhasin S et al. J Clin Endocrinol Metab. 2010;95:2536-2559.

Recommended Patients to Screen NOT Recommended to Screen • Type 2 diabetes mellitus • Treatment with medications, including

opioids and glucocorticoids • HIV-associated weight loss • End-stage renal disease and

maintenance hemodialysis • Moderate to severe chronic obstructive

lung disease • Infertility • Osteoporosis or low trauma fracture • Sellar mass

• General population

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Low T Screening Tools

• While the general population should not be screened, the following tools can aid in diagnosis for patients where screening is recommended – Endocrine Society guidelines recommend testing total

testosterone by2

Morning blood draw Total Testosterone <300 , repeated at least twice , confirm

the diagnosis of Hypogonadsim

2. Bhasin S et al. J Clin Endocrinol Metab. 2010;95:2536-2559. 9. Gavrilova N, Lindau ST. J Gerontol B Psychol Sci Soc Sci. 2009;64 (suppl 1):i94-i105.

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The Endocrine Society Clinical Practice Guideline (2010) for Evaluation of Adult Men

With Suspected Hypogonadism

BT, bioavailable testosterone; FSH, follicle-stimulating hormone; FT, free testosterone; LH, luteinizing hormone; SFA, seminal fluid analysis; SHBG, sex hormone-binding globulin; T, testosterone. Bhasin S et al. J Clin Endocrinol Metab. 2010;95:2536-2559.

History and physical (signs and symptoms)

Morning total T

Low T value

Exclude reversible illness, drugs, nutritional deficiency Repeat T [use FT or BT if suspect altered SHBG]

LH + FSH SFA [if fertility issue]

Confirmed low T (eg, total T 280–300 ng/dL) or FT or BT < normal (eg, FT 5–9 ng/dL)

Low T, low or normal LH + FSH (Secondary)

Low T, high LH + FSH (Primary) Normal T, LH + FSH

Follow-up

Normal T

Bhasin S, Journal of Clinical Endocrinology & Metabolism, Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline, 95, 6, 2010, 2536-2559. Copyright 2010, The Endocrine Society.

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Treatment Modalities for Male Hypogonadism

• Current TRT modalities – Application site and dose are not interchangeable across products

TRT Modality

Topicals • Gel • Patch • Solution

Injection Buccal system Subcutaneous pellets

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Discussion

• Efficacy profile • Application site • Safety profile

• Flexibility of dosing • Frequency of dosing • Method of administration

Which one of the following attributes do your patients say is most important to them?

JAMA Article

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In a retrospective cohort study of 8709 men ages 60 to 64 years with low serum testosterone concentrations (<300 ng/dL) undergoing coronary angiography, men who were subsequently prescribed testosterone had a higher risk of a composite outcome of all-cause mortality, MI, and stroke than men who did not take testosterone (hazard ratio [HR] 1.29, 95% CI 1.04-1.58); the results were similar after adjusting for the presence of coronary artery disease (CAD) [59]. Although the difference was significant, the absolute risk difference after one year of treatment was only 1.3 percent (11.3 versus 10 percent of patients had events in the testosterone and non-testosterone groups, respectively). A high percentage of men in the cohort had comorbidities, including over 80 percent with CAD. Men were prescribed testosterone gels, injections, but most commonly, patches

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A second retrospective cohort study examined records of 55,593 men who had been prescribed testosterone therapy. They found an increase in the relative risk of MI in men in the three months after starting testosterone therapy when compared with the rate of MI in the prior year (RR 1.36) [60]. However, the absolute excess risk was very low: an additional 1.25 cases per 1000 patient years. The increase in MIs was more pronounced in men over age 65 years (RR 2.19, absolute increase 6.25 additional cases per 1000 patient years versus 0.5 additional cases per 1000 patient years for those under age 65 years). In addition, men under age 65 years with known heart disease were at increased risk for MI (RR 2.07, absolute excess risk 10 additional cases per 1000 patient years). Pretreatment serum testosterone concentration was not one of the factors for inclusion in this study, so it is not known if the men were hypogonads

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Both retrospective studies are limited by the inability to verify diagnoses, indications for testosterone therapy, testosterone dose, and information on serum testosterone concentrations immediately before initiating therapy and while on therapy. This is particularly important because of the widespread and often inappropriate prescription of testosterone therapy for men with normal age-associated symptoms who donot have hypogonadism.

Endo Society/FDA opinion

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Based upon these data, the Endocrine Society and the US Food and Drug Administration (FDA) have issued statements alerting clinicians to the potential concerns about testosterone therapy and cardiovascular safety. While the FDA is investigating the available data, they have not concluded that testosterone therapy treatment increases the risk of stroke, MI, or mortality. Given the uncertainty of these data, we continue to recommend that testosterone be administered only to men who are hypogonadal, as evidenced by clinical symptoms and signs consistent with androgen deficiency and a subnormal morning serum testosterone concentration on three occasions as outlined above. The beneficial effects of testosterone in these men are clear, and there is no reason to suspect that increasing the serum testosterone to normal would increase the risk of any condition above normal

Prostate Monitorig

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While there are no data to suggest that hypogonadal men receiving testosterone therapy are at greater risk for developing adverse prostate outcomes,The Endocrine Society suggests the following monitoring for men over age 50 years receiving testosterone: ●For prostate cancer monitoring, digital rectal examination and measurement of serum PSA should be performed prior to starting testosterone therapy (as a baseline), three to six months after initiation of treatment, and then once a year or according to standard of care. The patient should be referred to a urologist for consideration of a prostate biopsy for any of the following: •A prostate nodule that is palpated at any time. •A serum PSA concentration (confirmed by a repeat value) that rises by more than 1.4 ng/mL in any one-year period. •A PSA velocity that is greater than 0.4 ng/mL per year for two or more years, beginning six months after initiation of testosterone therapy [2]. This recommendation assumes that the patient does not have prostatitis

Monitor Hematocrit

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Erythrocytosis — Erythrocytosis is a common adverse effect of testosterone administration, particularly with testosterone ester injections. It is of concern because the risk of venous thromboembolic disease is directly related to hematocrit . The hematocrit should be measured before initiating testosterone treatment, and if it is elevated, the cause should be sought before testosterone treatment is initiated. The hematocrit should be measured again after three to six months, and then yearly. If it increases above the upper limit of normal, a cause should be sought, and if none is found, the dose of testosterone should be decreased or stopped. The Endocrine Society Guidelines suggest stopping therapy if the hematocrit increases to ≥54 percent [2]. The hematocrit should be re-evaluated two months after the decrease or discontinuation. If the hematocrit normalizes, a lower dose of testosterone should be continued or restarted. If the hematocrit cannot be kept below the upper limit of normal, even when the serum testosterone concentration is at the low end of the normal range during testosterone treatment, phlebotomy can be considered

Q and A

• Thank you

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