Male Hormonal Contraceptives

Erica Leung Pharmacology 4AA3

Introduction
Research in male hormonal contraceptives since the 1970s Restricted to improvements in current methods (vasectomy, condoms) World population continues to increase Growing need for alternatives

Purpose

To provide a summary of the current research directions for male hormonal contraceptives (testosterone and progestin), and main conclusions from studies thus far
To discuss some of the implications within a cross-cultural context To discuss some of the issues and difficulties that may be hindering progress

Spermatogenesis

The production of sperm Occurs in the seminiferous tubules (testes) Diploid spermatogonia undergo a series of divisions and differentiation to form haploid spermatozoa Stored mainly in vas deferens Entire process takes 60-70 days; produce 120 million sperm per day

Hormones Involved

Androgens: (from Leydig cells) Testosterone (T) Gonadotrophins: (from anterior pituitary) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH)

Male Hormonal Contraception

Hormonal approaches rely on:

suppression of LH and FSH depletion of intra-testicular testosterone substitution of peripheral testosterone

The Ideal Contraceptive

The ideal male contraceptive should:

be rapidly effective and fully reversible be of acceptable modality (compliance) not interfere with other testosteronedependent 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

Testosterone Alone
The WHO conducted two studies; proof of concept for testosterone alone regimen Weekly intramuscular injections of testosterone enanthate for 6 months Those who achieved a threshold entered the efficacy phase

The WHO Studies

Study 1: Azoospermia (no sperm) 65% of subjects 1 pregnancy Study 2: Oligozoospermia (<3 million sperm/mL) 98% of subjects 4 pregnancies

Azoospermia: gold standard

Ethnic Differences

91% of East Asian males reached azoospermia, 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

Note

Resulted in supraphysiological (high) serum testosterone concentrations Side effects: low HDL, weight gain, acne Serum levels were variable

Frequent administration may not be acceptable (inconvenient)

Modalities

Injection: intramuscular (IM); eg. gluteus Transdermal: patch or gel; produces steady serum levels Implant: subcutaneous pellets; requires minor surgery; produces steady serum levels

Longer-Acting Testosterone
Testosterone enanthate Testosterone undecanoate dissolved in: tea seed oil (20.9 6 days) castor oil (33.9 6 days) Azoospermia still not readily achieved in Caucasian males

What next?

Progestins

Synthetic steroids that suppress sperm concentration by gonadotrophin-dependent and -independent mechanisms
1.
2. 3. 4.

Depot medroxyprogesterone acetate (DMPA) Norethisterone Levonorgestrel Desogestrel

Since progestins alone were not optimal, try combinations with testosterone

1. Testosterone + DMPA
Injecting DMPA + testosterone enanthate offered no additional benefit Injecting DMPA + longer-acting testosterone ester -> azoospermia after 20 weeks

DMPA injection with testosterone implant

DMPA results in slower return to baseline sperm concentrations after discontinuing use (stored in fat)

2. Testosterone + Norethisterone

Norethisterone acetate (NETA)- oral testosterone gel + NETA showed an unexplained 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

3. Testosterone + Levonorgestrel

Weekly injections of testosterone enanthate + oral levonorgestrel showed azoospermia lower doses also effective Levonorgestrel + testosterone patch OR testosterone undecanoate injection were not very effective
Current direction toward an implant with dual delivery of both compounds

4. Testosterone + Desogestrel

Oral desogestrel combined with testosterone enanthate was more effective at lower testosterone doses Testosterone pellets with oral desogestrel resulted in azoospermia for Caucasian and East Asian subjects pellets require surgery possible extrusion

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

Testosterone + GnRH Antagonists

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

Pros: GnRH antagonists achieve azoospermia sooner and recovery seems to be faster

Cons Daily/weekly injections, irritation, expensive

Compliance

Administration of testosterone and progestin often involves different modalities Users may find this inconvenient; unacceptable
Optimal to combine both into a single modality that is long-acting, such as an implant or a patch

Cross-Cultural Impact

Multi-center survey in UK, South Africa and China: (Martin et al., 2000) Males ranked implant as least popular in UK, South Africa and Hong Kong; most popular in Shanghai Males in UK and South Africa felt a pill would be convenient; China perceived it as inconvenient Females agreed that male pill would be a good idea, but were concerned that their partner would forget

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

Selected References
Anawalt, B.D., et al. (1999). A lower dosage levonorgestrel and testosterone combination effectively suppresses spermatogenesis and circulating gonadotrophin levels with fewer 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-induced azoospermia 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 potential male contraceptive: additive effects between desogestrel and testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid metabolism. J. Clin. Endocrinol. Metab., 84, 112-122.

Discussion Questions

Based on the information presented so far, is this something you would consider? Is the data convincing? What other studies would you want to see? Does protection from pregnancy necessarily require azoospermia? Do you perceive there to be any ethical issues associated with the clinical trials? What are the implications of STIs in hormonal contraceptives?