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Male Hormonal Contraceptives

Erica LeungPharmacology 4AA3


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Introduction

Research in male hormonal contraceptivessince the 1970s

Restricted to improvements in currentmethods (vasectomy, condoms)

World populationcontinues to increase

Growing need foralternatives


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Purpose

To provide a summary of the currentresearch directions for male hormonalcontraceptives (testosterone and progestin),

and main conclusions from studies thus far

To discuss some of the implications within across-cultural context

To discuss some of the issues and difficultiesthat may be hindering progress


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Spermatogenesis

The production of sperm

Occurs in the seminiferous tubules (testes)

Diploid spermatogonia undergo a series ofdivisions and differentiation to form haploidspermatozoa

Stored mainly in vas deferens Entire process takes 60-70 days; produce

120 million sperm per day


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Hormones Involved

Androgens: (from Leydig cells)

Testosterone (T)

Gonadotrophins: (from anterior pituitary)

Follicle-stimulating hormone (FSH)

Luteinizing hormone (LH)


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Male Hormonal Contraception

Hormonal approaches rely on:

suppression of LH and FSH

depletion of intra-testicular testosterone

substitution of peripheral testosterone


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The Ideal Contraceptive

The ideal male contraceptive should:

be rapidly effective and fully reversible

be of acceptable modality (compliance)

not interfere with other testosterone-dependent processes

have no short or long-term side effects

have no impact on eventual offspring

be more effective than current methods

be acceptable for both partners


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Testosterone Alone

The WHO conducted two studies; proof ofconcept for testosterone alone regimen

Weekly intramuscular injections oftestosterone enanthate for 6 months

Those who achieved athreshold entered theefficacy phase


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The WHO Studies

Study 1: Azoospermia (no sperm)

65% of subjects

1 pregnancy Study 2: Oligozoospermia (


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Ethnic Differences

91% of East Asian males reachedazoospermia, compared to 60% Caucasian

Reason for dichotomy is unclear feedback sensitivity to testosterone

germ cell apoptosis rate

diet and androgen production 5-reductase activity

It is necessary to investigate other methods


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Note

Resulted in supraphysiological (high) serumtestosterone concentrations

Side effects: low HDL, weight gain, acne

Serum levels were variable

Frequent administration may not beacceptable (inconvenient)


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Modalities

Injection: intramuscular (IM); eg. gluteus

Transdermal: patch or gel; produces steadyserum levels

Implant: subcutaneous pellets; requiresminor surgery; produces steady serum levels


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Longer-Acting Testosterone

Testosterone enanthate

Testosterone undecanoate dissolved in:

tea seed oil (20.9 6 days)

castor oil (33.9 6 days)

Azoospermia still notreadily achieved in

Caucasian males

What next?


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Progestins

Synthetic steroids that suppress spermconcentration by gonadotrophin-dependentand -independent mechanisms

1. Depot medroxyprogesterone acetate (DMPA)

2. Norethisterone

3. Levonorgestrel

4. Desogestrel

Since progestins alone were not optimal, trycombinations with testosterone


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1. Testosterone + DMPA

Injecting DMPA + testosterone enanthateoffered no additional benefit

Injecting DMPA + longer-acting testosterone

ester -> azoospermia after 20 weeks

DMPA injection with testosterone implant

DMPA results in slower return to baselinesperm concentrations after discontinuinguse (stored in fat)


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2. Testosterone + Norethisterone

Norethisterone acetate (NETA)- oral

testosterone gel + NETA showed anunexplained rebound in sperm conc.

Norethisterone enanthate (NETE)- injection

testosterone undecanoate + NETE

administered as a single injection azoospermia was achieved in twice as

many volunteers

injection interval up to 8 weeks


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3. Testosterone + Levonorgestrel

Weekly injections of testosterone enanthate+ oral levonorgestrel showed azoospermia

lower doses also effective

Levonorgestrel + testosterone patch ORtestosterone undecanoate injection were notvery effective

Current direction toward an implant withdual delivery of both compounds


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4. Testosterone + Desogestrel

Oral desogestrel combined with testosteroneenanthate was more effective at lowertestosterone doses

Testosterone pellets with oral desogestrelresulted in azoospermia for Caucasian andEast Asian subjects

pellets require surgery

possible extrusion


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Pros/Cons of Combination

Pros:

Reduces testosterone dose required

Avoids testosterone deficiency

Cons:

Progestin side effects

Requires 3-5 months to reach azoospermia Long recovery period back to baseline


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Testosterone + GnRH Antagonists

Prevents GnRH from acting at the anteriorpituitary; inhibits the release of LH and FSH

Pros:

GnRH antagonists achieve azoospermiasooner and recovery seems to be faster

Cons

Daily/weekly injections, irritation,expensive


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Compliance

Administration of testosterone andprogestin often involves different modalities

Users may find this inconvenient;unacceptable

Optimal to combine both into a singlemodality that is long-acting, such as animplant or a patch


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Cross-Cultural Impact

Multi-center survey in UK, South Africa andChina: (Martin et al., 2000)

Males ranked implant as leastpopular

in UK, South Africa and Hong Kong;mostpopular in Shanghai

Males in UK and South Africa felt a pillwould be convenient; China perceived

it as inconvenient Females agreed that male pill would

be a good idea, but were concerned thattheir partner would forget


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Concluding Remarks

An important field with global implications

Issues with study designs:

Observation periods vary widely Sample size too small (exploratory pilot studies)

Need more long-term studies

Inconsistent use of terms

Word oligozoospermia used in two different ways

Need a way to identify responders vs. non-responders


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Selected References

Anawalt, B.D., et al. (1999). A lower dosage levonorgestrel and testosterone combinationeffectively suppresses spermatogenesis and circulating gonadotrophin levels withfewer metabolic effects than higher dosage combinations.J. Androl., 20, 407-414.

Gu, Y.Q., et al. (2003). A multicenter contraceptive efficacy study of injectable

testosterone undecanoate in healthy Chinese men.J. Clin. Endocrinol. Metab

., 88,562-568.

World Health Organization. (1996). Contraceptive efficacy of testosterone-inducedazoospermia and oligozoospermia in normal men.Fertil. Steril., 65, 821-829.

World Health Organization. (1990). Contraceptive efficacy of testosterone-induced

azoospermia in normal men.Lancet

, 336, 955-959.

Wu, F.C.W., et al. (1999). Oral progestogen combined with testosterone as a potentialmale contraceptive: additive effects between desogestrel and testosteroneenanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipidmetabolism.J. Clin. Endocrinol. Metab., 84, 112-122.


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Discussion Questions

Based on the information presented so far,is this something you would consider?

Is the data convincing? What other studieswould you want to see?

Does protection from pregnancy necessarilyrequire azoospermia?

Do you perceive there to be any ethicalissues associated with the clinical trials?

What are the implications of STIs inhormonal contraceptives?

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