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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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