aromatase inhibitors in disclosures male...

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Aromatase Inhibitors in Male Infertility: The hype of hypogonadism?BEATRIZ UGALDE, PHARM.D.

H-E-B/UNIVERSITY OF TEXAS COMMUNITY PHARMACY PGY1

03 NOVEMBER 2017

PHARMACOTHERAPY ROUNDS

DisclosuresNo conflicts of interest to disclose

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Objectives•Describe adult male infertility and hypogonadism•Review the role of androgens in spermatogenesis•Outline current management strategies•Assess use of aromatase inhibitors in male infertility treatment•Recommend plan for patients with hypogonadism and infertility

3

Infertility1-5

•Inability of a couple to achieve pregnancy despite unprotected intercourse after 12 months•Affects 6.1 million couples in the United States• 10% reproductive aged adult• 15% of couples trying to conceive

•Male factor contributes to 50% of all cases •20% cases solely due to male factor

4

Common Terms in Male Infertility1,4,6,7

•Anorchia – Absence of both testes at birth•Azoospermia – complete or near lack of sperm production•Cryptozoospermia – type of azoospermia in which there is small amount of sperm only detected by centrifugation and concentration of the sample•Cryptorchidism – condition in which testicles have not descended•Oligospermia – Low sperm count <15 million spermatozoa/mL•Varicocele – Enlargement of veins in the scrotum

5APPENDIX A

Male Infertility1,3-5,8

•50-60% of these men have an identifiable cause•40-50% idiopathic•20% of men diagnosed with an endocrine problem•One-third of men have oligospermia or azoospermia• 43% of oligospermic due to hypoandrogenism• 45% azoospermic men due to spermatogenic dysfunction

•Degree of infertility variable and dependent on individual patient

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Why is this important?1,3,8,9

•Male partner factors are often neglected• High pregnancy rates with assisted reproductive techniques (ART)

•Area for improvement in current practice• Can often be reversed/cured• Risk of overlooking serious condition• ART can extensive and expensive and dangerous to mother and child• Treatment with medication cheaper than ART• Medications cost around $912 • In vitro fertilization: $19,324 for first cycle + $6955 per additional cycle• Many insurances do not cover fertility treatment

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Knowledge CheckMultiple choice:What percent of cases have some sort of male factor involvement?A. 20%B. 30%C. 50%D. 70%

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Diagnosis of male infertility4,7,10

•Medical history and physical examination• Involve urologist or specialist• Scrotal ultrasound• At least 2 semen analyses• Limits based on WHO criteria (Appendix B)• Abnormal sperm motility, morphology, and concentration

•Comprehensive andrological examination• If at least 2 abnormal semen analyses• Include testosterone and follicle stimulating hormone

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Causes of male infertility1

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Pre-testicular Testicular Post-testicular

Hypothalamic pituitary disorder Varicocele Ductular obstruction/scarring

Thyroid Disorder Trauma Retrograde ejaculation

Adrenal Disorder Infection Antibodies to sperm or seminal plasma

Drugs Drugs/Toxins Developmental abnormalities

Chromosomal abnormalities Androgen insensitivity

Developmental abnormalities Poor coital technique

Defective androgen production Sexual dysfunction, impotence

Idiopathic

Androgens and spermatogenesis

11

Bhasin et al. Harrison’s principles of internal med. 2015

Spermatogenesis1,6

•Testosterone (T) production and spermatogenesis controlled by the hypothalamic axis•Hypothalamus releases Gonadotropin releasing hormone (GnRH)• Pulsatile

•Stimulates anterior pituitary to secrete gonadotropins• Luteinizing hormone (LH)• Follicle stimulating hormone (FSH)

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APPENDIX C

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Spermatogenesis1,6

•FSH stimulates Sertoli cells • Production of paracrine growth factor • Support sperm growth

• Production of androgen binding globulin

•LH stimulates Leydig Cells• T produced• Binds to androgen binding globulin

• Secreted into seminiferous tubules and circulation

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APPENDIX C

T role in Spermatogenesis1

•T in seminiferous tubules are 80-100x more concentrated than in the general circulation• High concentration necessary for sperm production• Binds to androgen receptors

• Spermatogenesis in Sertoli cells• Inhibition of germ cell apoptosis

•T in the circulation provides negative feedback at hypothalamus and pituitary• GnRH, LH, FSH secretion

•T converted to estradiol (E2)• Aromatase: found in testes, prostate, bone, brain, adipose• E2 also provides negative feedback

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Fode et al. Pathophysiology of disease. 2014

APPENDIX D

Importance of Estrogen and Aromatase11

•Effects growth, development, and function of Leydig cells•Promotes maturation of spermatogonia•Paracrine function: inhibits aromatase activity in Sertoli cells•Autocrine function: low levels inhibit germ cell apoptosis•Lack of aromatase leads to impaired spermatogenesis

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Detrimental effects of Estrogen11

•Negative feedback on Hypothalamus-pituitary axis• ↓ FSH and ↓ LH Æ↓ spermatogenesis

•Inhibits spermiogenesis related genes and promotes spermatocyte apoptosis•Inhibitory effects on Sertoli and Leydig cell functions•Careful regulation needed for spermatogenesis

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Knowledge CheckMultiple choice:Aromatase is found in which of the following tissues?A. TestesB. BrainC. AdiposeD. Two of the aboveE. All of the above

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Hypogonadism

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Hypogonadism Etiology1,4

•Primary: • Testicular failure• Hypergonadotropic hypogonadism (HerH)

•Secondary• Hypothalamus-Pituitary Axis failure• Hypogonadotropic hypogonadism (HoH)

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Hypergonadotropic Hypogonadism1,4,5,12

•Characterized by:• ↑ FSH and/or LH• Leydig cell dysfunction

•Low T (< 300 ng/dL) and associated symptoms• ↓ libido, poor erections, hot flashes, low energy, weight gain, mood

change, sleep disturbance, ↓ body hair, infertility

•Deficient spermatogenesis

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HerH Etiology1,4

•Genetic•Testicular tumor•Trauma•Varicocele•Systemic diseases (liver cirrhosis, renal failure)•Iatrogenic: Surgery, radiotherapy, medications

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Hypogonadotropic Hypogonadism1,4,5,12

•Uncommon cause of male infertility•Characterized by either• ↓ GnRH production Æ↓ FSH and/or LH• Rare disorders of the pituitary (normal GnRH levels)• Result in primary deficiencies of FSH and LH

•Low T and associated symptoms•Deficient spermatogenesis

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HoH Etiology1,4

•Genetic• Abnormal synthesis/release GnRH (idiopathic)• Kallmann syndrome - failed GnRH axonal migration in fetal development• GnRH receptor abnormalities

•Pituitary mass lesions•Hyperprolactinemia•Anabolic steroid use•Radiotherapy•Obesity

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Current treatment strategies• TH E OPTIMAL E VALUATION OF TH E INFE RTILE MALE :

AME RICAN UROLOGY ASSOCIATION BE ST PRACTICE STATE ME NT.

• E UROPE AN ASSOCIATION OF UROLOGY GUIDE L INE S ON MALE INFE RTIL ITY.

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European Association of Urology Guideline-Based Treatment for hypogonadism4

•Provide T replacement for symptomatic patients with primary and secondary hypogonadism•In men with hypogonadotropic hypogonadism, induce spermatogenesis by an effective drug therapy (Human chorionic gonadotropin)•Do not use T replacement for the treatment of male infertility

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Treatment of Idiopathic Hypogonadism1,4

•Assisted reproductive treatment•Empirical medical treatment• Gonadotropin• Human chorionic gonadotropin (hCG) ± follicle stimulating hormone (FSH)

• Selective Estrogen Receptor Modulators (SERMs)• Clomiphene• Tamoxifen

• Aromatase Inhibitors• Anastrozole• Letrozole

•Lifestyle changes

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APPENDIX E 27

hCG

Rambhatla et al. Urol. 2016

Human Chorionic Gonadotropin14,15

•Mechanism of action:• Has the bioactivity of LH

•Labeled use:• Hypogonadotropic hypogonadism• Ovulation induction• Prepubertal cryptorchidism

•Off label use:• Spermatogenesis induction in hypogonadism

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Clinical Pharmacology

Human Chorionic Gonadotropin14,15

•Dose: IM injection• HH• 500-1000 units 3 times weekly for 3 weeks, then 2 times weekly for 3 weeks• 4000 units 3 times weekly for 6-9 months, then 2000 units 3 times weekly for 3

months• Spermatogenesis in idiopathic HH (off-label)• 1000-2000 units 2-3 times weekly until T levels normal (2-3 months)• May then add FSH if needed to induce spermatogenesis• Continue hCG dose required to maintain T levels

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Human Chorionic Gonadotropin5,14,15

•Side Effects• Elevated liver enzymes• Gynecomastia• Injection site reaction• Mood changes

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Human Chorionic Gonadotropin2,5,14,15

•Pros:• Approved for treatment of hypogonadotropic hypogonadism

•Cons:• High cost• Invasive

•Clinical use• Usually recommended if failed clomiphene or anastrozole

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Selective Estrogen Receptor Modulators13-15

•MOA: block negative feedback at hypothalamus and pituitary and indirectly enhance LH and FSH secretion•Most studied oral drugs in male infertility•Drugs:• Clomiphene• Tamoxifen

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Clomiphene citrate3,13-15

•Labeled use:• Infertility in women

•Off-label use:• Idiopathic oligospermia associated infertility

•Dose:• Optimal dosing not established: 12.5-400 mg/day• Common: • 25 mg 3 times weekly or once daily• 50 mg every other day up to once daily

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Clomiphene citrate5,13-15

•Side effects• Hot flashes• Headache• Nausea/Vomiting• Weight gain• Gynecomastia• Visual disturbances

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Clomiphene citrate2,3,5,13-15

•Pros:• Can ↑ FSH and LH• Inexpensive• Well tolerated• Most evidence• Longer duration in studies (15 months)

•Cons:• Can ↑ E2• May not be best in patients with elevated FSH• May worsen semen parameters

•Clinical Use: • Low testosterone and symptoms of low testosterone in male infertility

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Aromatase inhibitors2,3

•MOA: inhibit aromatase and ↓E2• May lead to stronger GnRH pulses and ↑FSH

•Drugs• Steroidal – irreversible• Testolactone• Formestane• Exemestane

• Nonsteroidal – reversible• Letrozole• Anastrozole

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Aromatase inhibitors13-15

•Labeled use:• Breast cancer

•Off label use:• Delayed puberty• Endometriosis• Infertility

•Dose:• Letrozole 2.5 mg daily• Anastrozole 1 mg daily• In practice: ½ – 1 tablet 2-3 times weekly

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Aromatase inhibitors13-15

•Half-life:• Letrozole: 48 hours• Anastrozole: 50 hours

•Side effects:• Headache• Hot flash• Hypercholesterolemia• Weight gain• Edema• ↓ bone density (long term in women)

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Pavlovich et al. J Urol. 2001.

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Testosterone:Estradiol Ratio

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Pavlovich et al. J Urol 2001Pavlovich CP, King P et al. Evidence of treatable endocrinopathy in infertile men. J Urol 2001;165:837-841

Objective Assess serum T:E2 ratio in infertile and fertile men and the effect of testolactoneon semen parameters

Design Non-controlled trial

Inclusion Azoospermic or oligospermic men (n = 63) with clinical evidence of male factor infertility including:• Small testes• Increased serum FSH (mean: 21.2 ± 1.8 IU/L)• Abnormal semen analysisFertile men (n= 40)• Age matched• Proved fertility• No evidence of testicular dysfunction

Intervention (n=45) 50 – 100 mg oral testolactone twice daily for 5 months

T:E2 Ratio16

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Outcome

Population characteristics

• Original population (n=63)• 43 azoospermic• 20 oligospermic

• Hormone analysis• 12 azoospermic• 12 oligospermic

Primary Outcomes • Hormonal evaluations: T, E2, T:E2, FSH, LH• Seminal parameters

Secondary Outcomes • Liver function testsT:E2 ratio (p<0.01) Infertile men (n = 24) Fertile men

6.9 ± 0.6 14.5 ± 1.2 (95% CI 7.2-21.8)FSH (p<0.01) 21.2 ± 1.8IU/L 5.5 ± 0.3 IU/L

T:E2 Ratio16

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Outcome Baseline Post Intervention P value

T (ng/dL) 303 396 <0.01

E2 (ng/L) 66 37 <0.01

T:E2 ratio 5.0 ± 0.3 12.7 ± 1.2 <0.01

Sperm motility 27.1 ± 5.9% 45.3 ± 5.8 <0.01

Sperm concentration (million/mL) 16.1 ± 5.3 28.9 ± 8.3 0.03

Semen volume (million/ejaculate) 20.1 ± 8.8 54.1 ± 23.9 0.08

LFTs • Mild ↑ transaminase in 6 patients• Indirect bilirubinemia in 2 patients• None more than 2 fold above normal

Author’s Conclusion:Aromatase inhibitors can improve semen parameters and increase the T:E2 ratios

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T:E2 Ratio16

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Strengths• T:E2 ratios not previously studied

Weaknesses• Small group, only 12 oligospermic

patients analyzed• No baseline characteristics• Varying etiologies, no exclusions• Non-randomized or controlled• Use testolactone• Single semen analyses• Possibility of sex hormone binding

globulin decrease• No side effect data reported

T:E2 Ratio16

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• An aromatase inhibitor can normalize the T:E2 ratio in men and may have an effect on semen parameters in oligospermic men

Overall conclusion

• What is the normal T:E2 ratio in men?• Do aromatase inhibitors affect SHBG levels?• Can the nonsteroidal aromatase inhibitors affect male

semen parameters and male infertility in men with decreased T:E2 ratios?

Questions remaining

Saylam B, et al. Fertil Steril. 2011.

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Letrozole and ↓T:E2Saylam B, Efesoy O, and Cayan S. The effect of aromatase inhibitor letrozole on body mass index, serum hormones, and sperm parameters in infertile men. Fertil Steril 2011;95:809-811.Objective • To investigate the effect of letrozole in BMI, serum hormones, and sperm

parameters in male infertility associated with ↓T:E2 ratiosDesign • Turkey

• Noncontrolled comparative trialInclusion • Infertile men with low T:E2 ratio (<10) (n=27)

• T < 330 ng/dLExclusion • Additional etiology (varicocele, ejaculatory duct obstruction)

• Female factor infertilityIntervention • All treated with 2.5 mg letrozole daily for ≥ 6 months

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Letrozole and ↓T:E217

Outcome


• Mean age 34.92 ± 6.66 (range: 26-49)• 17 azoospermic• 10 oligospermic

Primary outcome • Serum hormones: FSH, LH, T, E2, T:E2• BMI• Sperm parameters

Secondary outcomes • LFTs

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Letrozole and ↓T:E217Outcomes: all patients Baseline Post-intervention P value

BMI (kg/m2) 28.40 ± 3.86 28.90 ± 4.43 0.288

Testicular volume (mL) 15.39 ± 4.49 15.56 ± 4.47 0.213

Total motile sperm (million) 2.37 ± 1.14 6.76 ± 2.37 0.009

Motility (%) 7.03 ± 2.33 12.96 ± 2.91 0.017

Sperm count (million) 3.04 ± 1.18 7.00 ± 2.01 0.002

Ejaculate volume (mL) 2.55 ± 0.17 3.18 ± 0.19 0.001

FSH (mIU/mL) 9.16 ± 1.95 9.30 ± 1.94 0.360

LH (mIU/mL) 10.29 ±1.62 10.14 ± 1.60 0.117

T (ng/dL) 255 ± 23 527 ± 74 0.001

E2 (pg/mL) 25.93 ± 1.97 14.68 ± 2.01 0.001

T:E2 ratio 8 ± 0.4 39 ± 6.1 0.001

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Letrozole and ↓T:E217

Outcomes: Oligospermic Baseline (n=10) Post-intervention (n=10) P value

Total motile sperm (million) 6.41 ± 2.72 15.77 ± 5.01 0.016

Motility (%) 19.00 ± 4.13 24.00 ± 3.31 0.017



Pregnancy 0 2 --

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Outcomes: Azoospermic Baseline (n=17) Post-intervention (n=4) P value

Total motile sperm (million) 0 1.46 ± 1.23 0.253

Motility (%) 0 6.47 ± 3.34 0.071

Sperm count (million) 0 1.11 ± 0.69 0.125


Letrozole Side Effects17

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No severe side effects observed

Mild headache

(n=2)Author’s Conclusion: Letrozole may be used to effectively improve sperm parameters in infertile men with low serum T:E2 ratio and may lead to pregnancy, and may improve sperm count in azoospermia.

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Strengths• First study involving

letrozole• Excluded patients with

other etiology• Reported side effects• Reported pregnancies• Multiple samples

Weaknesses• Small groups• Non-randomized or

controlled

Letrozole and ↓T:E217 Letrozole and ↓T:E217

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• Letrozole may safely help improve sperm parameters in oligospermic men with ↓T:E2 in order to improve fertility and pregnancy rate

• Letrozole is well tolerated

Overall conclusion

• Should T:E2 <10 be the standardized cut-off?• Can anastrozole have similar effects?

Questions remaining

Shoshany et al.Fertil Steril. 2017.

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Anastrozole and ↓T:E211

Shoshany O, Abhyankar N, et al. Outcomes of anastrozole in oligozoospermic hypoandrogenic subfertilemen. Fertil Steril. 2017;107(3):589-594.Objective • To assess whether anastrozole can affect the sperm parameters in subfertile

hypoandrogenic men with ↓T:E2Design • Retrospective study

• Male fertility clinicInclusion • Hypoandrogenic subfertile men (n=86)

• Low T: <155 ng/dL• Either: low T:E2 <10 (n=78) or adverse reaction to clomiphene citrate (n=8)

Exclusion • History of sex chromosomal disorder• Past exogenous T use• Other concomitant hormonal treatment

Intervention • Anastrozole 1 mg daily for 4 months

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Outcome


• Median age: 37 (range: 32-41)• Mean duration of unprotected intercourse: 24 months (18-48)• 50 oligospermic• 28 azoospermic• 8 cryptozoospermic

Outcomes • Hormone analysis: total T, bioavailable T, E2, SHBG, albumin , FSH, LH• Semen analysis

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Outcome Baseline 3 week 4 month P value

Total T (ng/dL) 258.4 ± 10.8 509.2 ± 20.4 449.4 ± 19.5 <0.0001

Bioavailable T (ng/dL) 128.8 ± 4.7 297.5 ± 12.7 -- <0.0001

E2 (pg/mL) 40.8 ± 1.9 24.6 ± 2.1 23.2 ± 2.2 <0.0001

T:E2 6.98 ± 0.33 34.5 ± 6.5 24.2 ± 3 <0.0001

SHBG (nmol/L) 25.6 ± 1.1 24.9 ± 1.2 -- Not significant

LH (IU/L) 6.41 ± 0.89 10.7 ± 1.1 -- <0.0001

FSH (IU/L) 12.4 ± 2 19.4 ± 2.3 -- <0.0001

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Outcome Baseline 3 week 4 month P valueVolume (mL) 2.56 ± 0.22 -- 2.32 ± 0.25 NS

Concentration (million/mL) 4.7 ± 1.2 -- 13.1 ± 2.9 0.001

Motility (%) 39.9 ± 5 -- 40.5 ± 4.8 NS

Total motile count (million) 4.6 ± 1.3 -- 8 ± 3.4 <0.01

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• In oligospermic men only (n = 21)• Total motile count correlated with ↑T:E2 (P<0.0001)

• Controlled for Age and FSH concentration• Did not correlate to any other outcome

Anastrozole Side Effects11

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Bilateral ankle swelling, resolved with continued

treatment (n = 1)

Decreased libido, irritability, depression, bilateral breast

tenderness,ocular pruritus/pain, and

dry mouth (n = 1)

Paradoxical increase in E2 (n = 1)

Joint and tendon pain, and swelling in limbs

(n=2)

Author’s Conclusion: Anastrozole improved endocrine parameters in men with hypoandrogenism and sperm parameters in oligospermicmen. Total motile count correlated to ↑T:E2, thus arguing for a physiologic effect of treatment.

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Strengths• Excluded patients with

other etiology• Side effects reported• 2 semen samples per

patient• Evaluated SHBG levels

Weaknesses• Retrospective,

noncontrolled• Small group for seminal

parameters• Varicocele etiology• Did not report pregnancy

Anastrozole and ↓T:E211 Anastrozole and ↓T:E211

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• Anastrozole may help improve endocrinopathy and seminal parameters in oligospermic men.

• Anastrozole is well toleratedOverall

conclusion• Which is more effective, anastrazole or letrozole,

improving seminal parameters and infertility?• Which is better tolerated?• Can aromatase inhibitors improve sperm retrieval in

azoospermic men?

Questions remaining

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Gregoriou et al. Fertil Steril. 2012.

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Anastrozole vs LetrozoleGregoriou O, Bakas P, et al. Changes in hormonal profile and seminal parameters with use of aromatase inhibitors in management of infertile men with low testosterone to estradiol ratios. Fertil Steril. 2012;98(1):48-51Objective • To compare the effects of 2.5 mg letrozole with those of 1 mg anastrozole daily

Design • Prospective, nonrandomized study

Inclusion • Infertile men (n=29) • T:E2 <10• T<300

Exclusion • Abnormal karyotype analysis• Y chromosome microdeletion

Intervention • 2.5 mg letrozole daily for 6 months (n=15)• 1 mg anastrozole daily for 6 months (n=14)

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Anastrozole vs Letrozole18

Outcome

Baseline population • None reported

Primary outcomes • Serum hormones: FSH, LH, T, E2• Seminal analysis

Secondary outcomes • Liver function tests monthly

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Letrozole18Outcome Pre-intervention Post-intervention P value

BMI (kg/m2) 29.86 ± 2.53 30.1 ± 2.13 >0.05


FSH (mIU/mL) 8.35 ± 2.03 8.41 ± 1.95 0.93

LH (mIU/mL) 9.55 ± 1.84 9.28 ± 1.80 0.69

T (ng/dL) 275 ± 29 495 ± 65 <0.001

E2 (pg/mL) 26.7 ± 1.75 14.98 ± 2.58 <0.001

T:E2 ratio 9 ± 0.2 36 ± 4.5 <0.001

Ejaculate Volume (mL) 2.85 ± 0.36 3.35 ± 0.2 0.005


Motility (%) 11.05 ± 2.48 22.13 ± 4.37 0.001

Total functional sperm fraction (million)

1.71 ± 0.87 2.51 ± 1.09 0.013

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Anastrozole18Outcome Pre-intervention Post-intervention P value

BMI (kg/m2) 30.14 ± 3.1 30.0 ± 2.75 >0.05


FSH (mIU/mL) 8.35 ± 1.95 8.45 ± 1.93 0.89

LH (mIU/mL) 11.15 ± 1.58 11.01 ± 1.53 0.81

T (ng/dL) 265 ± 25 513 ± 65 <0.001

E2 (pg/mL) 24.1 ± 20.1 15.15 ± 1.95 <0.001

T:E2 ratio 8 ± 0.5 34 ± 5.9 <0.001

Ejaculate Volume (mL) 2.40 ± 0.15 3.18 ± 0.52 <0.001

Sperm count (million) 4.15 ± 3.38 8.9 ± 2.11 <0.001

Motility (%) 12.35 ± 3.89 22.85 ± 3.38 <0.001

Total functional sperm fraction (million)

1.91 ± 1.25 2.41 ± 1.06 0.005

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Letrozole and Anastrazole Side Effects18

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Letrozole↑ liver

enzymes (n=1)

Transient weakness

(n=2)

Nausea x 10 days

(n=1)

Mild headache

(n=2)

Anastrazole↑ liver

enzymes (n=2)

Mild diarrhea x 3 days (n=1)

Transient nausea (n=2)

Mild headache

(n=1)

Author’s Conclusion:Anastrozole and letrozole are equally effective in improving T levels and seminal parameters in men with severe oligospermia, low T levels, and normal gonadotropins.

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Strengths• Compared letrozole and

anastrozole• 2 semen samples per patient• Reported side effects• All patients were oligospermic

Weaknesses• Small groups• No baseline characteristics

reported• Not randomized or controlled• Not powered to detect

statistical significance between the two differences

• Pregnancies not reported


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• Aromatase inhibitors may help improve seminal parameters and endocrinopathy in oligospermic men with low T:E2 ratios.

• Both aromatase inhibitors seem well tolerated

Overall conclusion

• Are anastrazole and letrozole equally effective, in improving seminal parameters and infertility?

• Is one better tolerated than the other?

Questions remaining


Literature Summary

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Summary of Literature11,16-18

Study Pavlovich et al. Saylam et al. Shoshany et al. Gregoriou et al.

Design Prospective Prospective Retrospective Prospective

Drug Testolactone Letrozole Anastrozole Letrozole Anastrozole

Dose 50 – 100 mg daily 2.5 mg daily 1 mg daily 2.5 mg daily 1 mg daily

Duration 5 months ≥ 6 months 4 months 6 months

Patients N = 63;24 N=27 N=86;21 N=15 N=14

Diagnosis Oligospermic, azoospermic

Oligospermic, azoospermic

Oligospermic, azoospermic, cryptozoospermic

Oligospermic

# semen samples 1 3 2 2

Side effects reported

No Yes Yes Yes

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Summary of Literature11,16-18Outcome Pavlovich et al. Saylam et al. Shoshany et al. Gregoriou et al. Drug Testolactone Letrozole Anastrozole Letrozole AnastrozoleBMI -- NS -- NS NSTesticular volume -- NS -- NS NSFSH -- NS ↑ NS NSLH NS NS ↑ NS NST ↑ ↑ ↑ ↑ ↑ E2 ↓ ↓ ↓ ↓ ↓T:E2 ratio ↑ ↑ ↑ ↑ ↑Ejaculate volume NS ↑ NS ↑ ↑Sperm count ↑ ↑ ↑ ↑ ↑Motility ↑ ↑ NS* ↑ ↑SHBG -- -- NS -- --TFSF -- -- -- ↑ ↑

71APPENDIX F *↑total motile count

Aromatase inhibitors2,3,5,13-15

•Pros:• ↑ T without ↑ E2• ↑ T:E2 ratio• Inexpensive

•Cons:• Less evidence• No consistent regimen

•Clinical use: • Hypogonadism with low T:E2 ratio (<10)

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APPENDIX E 73

hCG

Rambhatla et al. Urol. 2016

Knowledge CheckMultiple Choice:Which of the following medications has an FDA indication for male hypogonadism? [Select all that apply]A. ClomipheneB. AnastrozoleC. hCGD. Testosterone

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Knowledge checkMultiple choiceAromatase inhibitors may increase the following parameters except:A. Sperm countB. Testicular volumeC. Testosterone:Estradiol ratioD. Testosterone

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Treatment algorithm

Mal

e in

fert

ility

and

hy

pogo

nadi

sm

T:E2 <10 or increased E2 levels?

Yes Anastrozole

Failed treatment Human chorionic gonadotropin

No ClomipheneFailed treatment Human chorionic

gonadotropin

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Conclusion•T:E2 ratio seems to be correlated with infertility in some oligospermic infertile men•T:E2 < 10 should be used as a guide •Aromatase inhibitors may help oligospermic men• ↑ T • ↓ E2• ↑ T:E2• ↑ sperm count• ↑ sperm motility

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Future research•Prospective randomized trials•Normal/optimal T:E2 ratio•Different dosing schedules• 2-3 times weekly vs daily

•Aromatase inhibitors and sperm retrieval in azoospermic men•Tolerability and long term effects• Bone density• Hypercholesterolemia

•Guideline implementation

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Acknowledgments•Evaluator• Sharon Rush, R.Ph.

•Residency Program Director• Nathan Pope, Pharm.D., BCACP,

FACA

•Preceptors• James Weems, R.Ph.• Amanda Stallings, Pharm.D.• Gretta Leckbee, R.Ph.• Jennifer Wilbanks, R.Ph.• Lauren Clark, Pharm.D.• Mark Comfort, Pharm.D.

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Questions?

Aromatase Inhibitors in Male Infertility: The hype of hypogonadism?BEATRIZ UGALDE, PHARM.D.

H-E-B/UNIVERSITY OF TEXAS COMMUNITY PHARMACY PGY1

03 NOVEMBER 2017

PHARMACOTHERAPY ROUNDS

aromatase inhibitors in disclosures male...

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