MALE CONTRACEPTION UPDATE

Summaries of new peer-reviewed publications

Endocrinological approaches
Dr. Jim Dalton introduced his group’s work on a selective androgen receptor modulator (SARM) at the “Future of Male Contraception” conference in Seattle last fall.  Now the group reports on the pharmacologic effects and contraceptive efficacy of a combined regimen of the SARM (S-23) and estradiol benzoate (EB) in male rats.  The regimen suppressed LH and FSH levels, while “[increasing] bone mineral density and lean mass, [and reducing] fat mass in a dose-dependent manner.” The contraceptive effect was fully reversible. “This is the first study to show that a SARM combined with EB is an effective and reversible regimen for hormonal male contraception in rats. The beneficial effects of S-23 on the muscle, tissue selectivity, and favorable pharmacokinetic properties make it a strong candidate for use in oral male contraception.”
Preclinical Characterization of a (S)-N-(4-Cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro, 4-chlorophenoxy)-2-Hydroxy-2-Methyl-Propanamide: A Selective Androgen Receptor Modulator for Hormonal Male Contraception.
Jones A, Chen J, Hwang DJ, Miller DD, Dalton JT.
Endocrinology. 2008 Sep 4. [Epub ahead of print]
PMID: 18772237

Supporting endocrinological research
Validation of a method of simultaneous measurement of serum T and DHT levels using “liquid-liquid extraction followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) with positive-mode electrospray ionization… The lower limit of quantification was 0.069 nmol/L for both steroids… The reference intervals (mean +/- 2 SDs) determined for T and DHT were 9.2-33.7 nmol/L and 0.47-2.65 nmol/L, respectively, for 113 healthy adult men.”
Simultaneous Measurement of Serum Testosterone and Dihydrotestosterone by Liquid Chromatography Tandem Mass Spectrometry.
Shiraishi S, Lee PW, Leung A, Goh VH, Swerdloff RS, Wang C.
Clin Chem. 2008 Sep 18. [Epub ahead of print]
PMID: 18801940

A study of the histological effects of treatment with FSH antiserum on rat and bonnet monkey epididymides. Observed changes “included a decrease in the size of the tubule lumen,… intensive vacuolization, and uneven surface of the luminal epithelium… These results suggest that cauda epididymis is a target for FSH action.”
Effect of deprivation of endogenous follicle stimulating hormone on rat epididymis: a histological evaluation.
Dahia CL, Petrusz P, Hall SH, Rao AJ.
Reprod Biomed Online. 2008 Sep;17(3):331-7.
PMID: 18765003

Cell adhesion targets
A controlled trial of adjudin in adult male rabbits investigating the pharmacokinetics, contraceptive efficacy, reversibility, and side effects of two modes of delivery – oral versus IV administration.  “The intravenous treatment showed much severe disturbance of spermatogenesis compared to gavage treatment, which was correlated with bioavailability of the drug.  The areas under curves (AUCs) for intravenous injection or gavage were 20.11 +/- 1.90 and 2.23 +/- 0.45 mg.h.L-1, respectively. These results illustrate the potential of adjudin as a male contraceptive and the efficacy is associated with the bioavailability of the drug.”
Adjudin Targeting Rabbit Germ Cell Adhesion as a Male Contraceptive: a Pharmacokinetic Study.
Hu GX, Hu LF, Yang DZ, Li JW, Chen GR, Chen BB, Mruk DD, Bonanomi M, Silvestrini B, Cheng CY, Ge RS.
J Androl. 2008 Sep 18. [Epub ahead of print]
PMID: 18802200

Motility targets
“This review summarizes the ion channel currents that have been directly measured in mammalian sperm, and their physiological roles in fertilization. The predominant currents are a Ca²⁺-selective current requiring expression of the 4 mCatSper genes, and a rectifying K⁺ current with properties most similar to mSlo3. Intracellular alkalinization activates both channels and induces hyperactivated motility.”
Ion channels that control fertility in mammalian spermatozoa.
Navarro B, Kirichok Y, Chung JJ, Clapham DE.
Int J Dev Biol. 2008;52(5-6):607-13.
PMID: 18649274

“Several small molecules (fertilization promoting peptide [FPP], adenosine, calcitonin and adrenaline), found in various body fluids including seminal plasma, have been shown to regulate capacitation in vitro. They initially accelerate capacitation but then inhibit spontaneous acrosome loss, allowing spermatozoa to maintain their fertilizing potential. Specific receptors for all these molecules are present on mammalian spermatozoa and their activation by the appropriate ligands leads to modulation of membrane-associated adenylyl cyclase activity and production of cAMP, stimulating cAMP production in uncapacitated cells and inhibiting it in capacitated cells.”
The role of small molecules in sperm capacitation.
Fraser LR.
Theriogenology. 2008 Sep 3. [Epub ahead of print]
PMID: 18775560

Binding / fusion targets
“Emerging evidence indicates that [cell surface architecture associated with capacitation] is facilitated by molecular chaperone-mediated assembly of a multimeric receptor complex on the sperm surface… [We] provide the first evidence that chaperones partition into detergent resistant membrane fractions (DRMs) within capacitated mouse spermatozoa and co-localize in membrane microdomains enriched with the lipid raft marker, G(M1) ganglioside … [Isolated DRMs] possessed the ability to selectively bind to the zona pellucida of unfertilized, but not fertilized, mouse oocytes. A comprehensive proteomic analysis of the DRM fractions identified a total of 100 proteins, a number of which have previously been implicated in sperm-oocyte interaction.”
Composition and significance of detergent resistant membranes in mouse spermatozoa.
Nixon B, Bielanowicz A, McLaughlin EA, Tanphaichitr N, Ensslin MA, Aitken RJ.
J Cell Physiol. 2008 Aug 25. [Epub ahead of print]
PMID: 18726997

“[We] show that sperm-egg fusion is mediated by vesicles containing CD9 that are released from the egg and interact with sperm. We demonstrate that the CD9(-/-) eggs, which have a defective sperm-fusing ability, have impaired release of CD9-containing vesicles. We investigate the fusion-facilitating activity of CD9-containing vesicles by examining the fusion of sperm to CD9(-/-) eggs with the aid of exogenous CD9-containing vesicles. Moreover, we show, by examining the fusion of sperm to CD9(-/-) eggs, that hamster eggs have a similar fusing ability as mouse eggs.”
The fusing ability of sperm is bestowed by CD9-containing vesicles released from eggs in mice.
Miyado K, Yoshida K, Yamagata K, Sakakibara K, Okabe M, Wang X, et al.
Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):12921-6. Epub 2008 Aug 26.
PMID: 18728192

Semen analysis standardization
A comparison of the accuracy of azoospermia determination using microscopic examination of centrifuged versus uncentrifuged semen samples post-vasectomy. “We conducted a secondary analysis of data from 3,205 semen analyses performed during a randomized clinical trial of 2 vasectomy techniques… Of 2,104 samples categorized as azoospermic before centrifugation, post-centrifugation analysis demonstrated that all but 4 (99.8%) were azoospermic or had a sperm concentration of less than 100,000 sperm per ml… Microscopic examination of uncentrifuged specimens is a reliable method for identifying semen samples after vasectomy with more than 100,000 sperm per ml.” These results suggest that trials of male contraceptive methods that suppress spermatogenesis can rely on microscopic examination alone to determine whether subjects can enter the efficacy phase.
Diagnostic Accuracy of an Initial Azoospermic Reading Compared With Results of Post-Centrifugation Semen Analysis After Vasectomy.
Steward B, Hays M, Sokal D.
J Urol. 2008 Sep 17. [Epub ahead of print]
PMID: 18804227

 

BIOQUAL’s male contraceptive leads: nonhormonal L-CDB-4022 and dimethandrolone undecanoate (DMAU)

BIOQUAL, a research facility in Rockville, MD, is pursuing two possible male contraceptive leads.  Both leads are orally available: an indenopyridine currently known as L-CDB-4022, and the androgen DMAU.  Both compounds were discussed at last September’s “Future of Male Contraception” conference.  What’s new?  What does the future hold?

L-CDB-4022
While doing safety-screening of potential new antihistamines, scientists at Sandoz discovered that a certain class of drugs (indenopyridines) had anti-fertility effects.  Last September BIOQUAL reported that in their tests of of an orally-active indenopyridine derivative, L-CDB-4022, monkeys showed reduction of sperm to levels indicative of infertility, and a complete loss of sperm motility that lasted for 6 weeks, after only 7 days of treatment.  All monkeys regained baseline sperm production by week 16.

Since the conference, the BIOQUAL team has focused on investigating the compound’s mechanism of action, and what conditions make it reversible or irreversible.  Dr. Sheri Hild reports the technical details:

“We have published a paper in Endocrinology… [concluding] that L-CDB-4022 affects multiple proteins and pathways in the rat testis, leading to germ cell loss. L-CDB-4022 induces rapid activation of the ERK-MAPK signaling pathway, followed by down-regulation of prosurvival factors such as the membrane form of stem cell factor (SCF), and up-regulation of the Fas-mediated apoptotic pathway. L-CDB-4022 also affects various adherens junction proteins that are involved in Sertoli-germ cell adhesion and disrupts Sertoli cell microtubule structure. Additional experiments will be required to determine whether the blood-testis-barrier has been disrupted by L-CDB-4022 in male rats leading to irreversible infertility.' Dr. Koduri also presented a poster at the 2008 Endocrine Society meeting entitled 'Role of testosterone in the mechanism of action of L-CDB-4022, a potential nonhormonal oral male contraceptive, in the rat.' The results of this preliminary study suggest that testosterone's regulation of tyrosine tubulin, Fas, integrinβ1, and γ-laminin contributes to L-CDB-4022-induced irreversible infertility in rats.”

Dr. Barbara Attardi adds that the team is continuing investigate the mechanism of action using cultured Sertoli cell isolated from 16 day-old rats. They are exploring what intracellular signaling pathways are affected by the drug, and have some interesting preliminary results.

But trouble looms: larger quantities of drug will be needed to do further toxicology and monkey efficacy studies, and the current chemical synthesis and purification are tedious, costly, and inefficient. A stereospecific synthesis method is needed.  But BIOQUAL is not a chemical synthesis facility, so streamlining the production of the compound will have to be contracted out. Success is likely but not guaranteed, and the process will be expensive.

The Contraception and Reproductive Health Branch (CRHB) of NICHD has funded BIOQUAL's work so far. Will the CRHB have enough resources to fund this next step?  Stay tuned.

Dimethandrolone undecanoate (DMAU)
The BIOQUAL team is also working on orally active androgens.  At last September's conference, Dr. Attardi presented data showing that DMAU has dual hormonal activity, with both androgenic and progestational effects. This prompted a study to investigate its potential as a male oral contraceptive in rabbits; lower doses of DMAU, but not a high dose, suppressed spermatogenesis, resulting in reversible infertility.

Dr. Barbara Attardi reports that since the conference, the team has moved several steps forward in animal tests on both DMAU and a second androgen:

“We are working on a second androgen ester (11β-methyl-19-nortestosterone 17β-dodecylcarbonate) as well as DMAU. A manuscript concerning the failure of these androgens to be aromatized has just appeared in the Journal of Steroid Biochemistry and Molecular Biology (2008: 110, 212-220). Both androgens are currently being tested in cynomolgus monkeys in 28-day toxicology studies by a contract laboratory. This is preliminary to phase I trials in men. We are also doing various toxicokinetic studies in-house for 11β-methyl-19-nortestosterone 17β-dodecylcarbonate in rats and rabbits (similar studies have already been completed for DMAU). DMAU has also been tested at a lower dose in the rabbit antifertility study, and we have initiated testing of 11β-methyl-19-nortestosterone 17β-dodecylcarbonate for antispermatogenic effects in this model.”

A new collaboration with Dr. Al Matsumoto’s lab a the University of Washington may bolster some of the potential non-contraceptive uses for DMAU.  The tests will examine the compound’s effects on bone mineral density and muscle mass in castrate rats. 

Which androgen will progress faster, DMAU or GTx's selective androgen receptor modulator? Will funding become available to develop the higher-output production process needed for continued research with L-CDB-4022? Watch for updates on this NICHD-funded work in future editions of this newsletter.

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Reproductive health professionals hear about your work

MCIP and the Male Contraception Coalition drew lots of comment at this month's Association of Reproductive Health Professionals conference, with our lifesize "Average Joe" poster reminding people that men are the other half of family planning. Dr. Trent MacKay's subsequent "Lunch and Learn" seminar on male contraceptive research was one of the best-attended lunchtime breakout sessions, with clinicians and researchers sitting on the floor and spilling out the door – those in the photo were just the beginning!  Dr. MacKay gave an overview of NICHD's program and fielded lively questions on the pros and cons of hormonal methods.  The general consensus reflected research findings that a majority of men will consider a method if it is practical and safe.

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Press: The Times (London)

We've been hearing from friends as far away as Berlin who saw "Sperm Warfare," an enthusiastic, lengthy piece on male contraception research in The Times (London). The article describes hormonal methods, the Vassonic device, the IVD, RISUG, ultrasound, and HIFU. The author missed out on a couple of depressing updates – that HIFU nonsurgical sterilization is stalled due to lack of funding, and the American IVD design is missing in action – but new funding could change that.

The comments offer an interesting glimpse of public opinion on these emerging male contraceptive methods:

“In my opinion, contraception and STD prevention are two separate things. Fidelity is all very well, but not all of us have met Mr/Ms Right yet. I had my tubes tied when I was 24, for contraception, but I still use condoms for STD prevention. There is no harm in doubling up - women do it all the time.”          - L. Porter, London, UK

“Bring it on. Anything that can help couples avoid accidental pregnancies and men avoid 'accidental' pregnancies by both parties using a reliable form of birth control that doesn't have the lack of appeal of condoms has to be a good thing. The ultrasound sounds the most marketable.”        - Chris Jackson, London, UK

Read more:
Sperm warfare
The Times Online, 20 September

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Press: Sydney Morning Herald

This humorous article points out that 1 in 3 Australian men in their 40s and 50s has gotten a vasectomy, and gives the credit to "some fairly good education and some assertive Australian women!”

“Only one in six Americans over 35 has had the snip, but single 20-something American men are turning to the operation…, US publications including the Chicago Tribune and men.style.com have reported. Social analysts say this is because getting a chick pregnant would, like, totally not rock, dude…While men taking on responsibility for contraception is admirable, vasectomies are not always easy to reverse, and young men's scrotums being punctured left, right and centre like party balloons is not an ideal state of affairs.”

Check out this spirited Australian take on the alternatives under development.

Read more:
It's hip to get the snip
Sydney Morning Herald, 29 September

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Press: Feministing.org

Last month's article in Time (US) inspired bloggers at Feministing.org to ask: "Would the men in your lives (boyfriends, partners, brothers, friends) be open to new forms of birth control?" Fifty men and women weighed in with articulate comments, giving a sense of what's on the public's mind – from frustration with double standards for drug development to thoughts on possible roles for male contraceptives in the family planning mix. A sample:

"It's not just the demand that drug manufacturers are looking at. It's whether or not they will be able to recoup cost of drug development and make huge profits…  Success in the US market would mean that male birth control would need to be seen as a medical necessity. Otherwise insurers could refuse to pay (as they are trying to do for women's contraceptives) leaving men to foot the bill for a product that will most likely be more expensive than the female counterpart. Good luck with that.  The obvious solution is for governments to subsidize part of the research like the US does for Orphan drugs (drugs for rare disorders that have a limited market yet serve an unmet medical need). Also, contraception needs to be considered a medical necessity so that insurers are obligated to a least cover part of the cost.  But mind you there is probably another Viagra type product in the pipeline somewhere so all is not lost."          - Sarah

"Most men, rightly or wrongly, are way too superstitious to trust a 'temporary' contraceptive… especially when there's a temporary one already available, and, oh bonus, it protects you against AIDS, too. They call it a condom."          - Roxie

"The argument about hormonal male BC not preventing STDs is moot, a given, we already know that. If someone isn't in a relationship its just a good idea to double up (condom and BC). There are so many combinations and situations where male BC would be awesome. "          - Spike

Read more:
Big pharma limits birth control options for men
Feministing.org, 6 August

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More press coverage!

Chicago Tribune report of younger men turning to vasectomy, with discussion of pros and cons, including counseling issues.  “Jeremy Youngman, a 32-year-old tattoo artist in Downers Grove, likes his birth control the way he likes his body art: permanent…”
Vasectomies: Word of caution on birth-control procedure
Chicago Tribune, 26 August

“There is an entire multimillion-dollar industry out there that won't put money on the odds that men are willing to take responsibility for the number of children they father… It would be different if Big Pharma got their 1962-tinged portrait of today's man right, but their own studies tell us otherwise.”
Why macho firms push Viagra instead of the pill for men
The New Zealand Herald, 10 September

“What is clear is the media, bloggers and researchers are talking about male contraception-the potential successes, failures and implications… Where is the larger, coordinated advocacy for the future of these technologies and where is the broader support for the rights of men to control their fertility and become more active family planners?  As reproductive health and rights advocates… we can lend our knowledge, advocacy and lessons learned from the struggle to achieve women's reproductive rights to this new revolution.”
Male birth control: Seeds of revolution?
RH Reality Check, 16 September

A men’s rights take on the need for additional male contraceptive options. “As a man, there are traditionally two methods of birth control; condoms and relying on a woman’s word that she has reliable birth control. There are clear drawbacks to both methods.… [Additional] choice for men means better parenting for children because more men will be able to become fathers when they are married, willing, and stable- a huge benefit for children and society as a whole.”
Vasectomies: The only choice left for men?
Men’s News Daily, 19 September

More opinions on the idea of new options for men, inspired by press reports of Prof. Derek Abbott’s early-stage research.  “I do think there are men that want alternative forms of birth control. I know many of my boyfriends would have preferred other methods to birth control than me using hormonal birth control that made me irritable and have a decreased sex drive…”
Remote control male birth control. Seriously.
Feministing.org, 23 September

Dr. Joseph Tash and Dr. Gunda Georg’s NIH-funded work on H2-gamendazole, and student reaction to the idea.
Balancing the burden of birth control
The University Daily Kansan, 25 September

A survey of South Korean women age 19-34 found 45% believe contraception should be a man’s responsibility, “seen as a carry-over from the country’s male-dominated Confucian culture, which exerts significant control over female sexuality.”
Korean Women Say Birth Control is ‘Men’s Responsibility’
EcoWorldly, 27 September

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Calendar of events

Planning to attend a male contraception or andrology-related event that's not listed here? Let us know so we can post it and alert your colleagues to interesting upcoming events.

October 1-3	Androgens 2008, 5th Biennial Meeting on Androgen Receptor Function; Rotterdam, The Netherlands
October 15-17	14th International Workshop on the Development and Function of the Reproductive Organs; Villa Mondragone, Italy
October 15	Deadline for International Congress of Andrology abstract submission
October 22-25	30th Annual British Adrology Society Meeting; Gijon, Spain
October 25-28	2008 American Public Health Association Annual Meeting & Exposition; San Diego, CA, USA
November 8-12	American Society for Reproductive Medicine 64th Annual Meeting; San Francisco, CA, USA
November 24	Deadline for European Congress of Endocrinology abstract submission
November 26-28	5th European Congress of Andrology; Rome, Italy
December 1	Deadline for North American Testis Workshop abstract submission
December 4-6	Second Congress of the Asia-Pacific Council on Contraception (APCOC); Macao, China
December 15	Deadline for World Congress on Reproduction abstract submission
2009
March 5-8	13th World Congress on Human Reproduction; Venice, Italy
March 7-10	9th International Congress on Andrology; Barcelona, Spain
April 1-4	20th North American Testis Workshop; Philadelphia, PA, USA
April 4-7	34th American Society of Andrology meeting; Philadelphia, PA, USA
April 25-29	11th European Congress of Endocrinology; Istanbul, Turkey
May 31	Deadline for Asia-Pacific Forum on Andrology abstract submission
October 10-13	Third Asia-Pacific Forum on Andrology; Nanjing, China

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Editors

Kirsten Thompson, Director of the Male Contraception Coalition (MCC)
Email: Kirsten@MaleContraceptives.org
Phone: +1 (443) 858-1183

Elaine Lissner, Director of the Male Contraception Information Project (MCIP)
Email: Lissner@NewMaleContraception.org
Phone: +1 (415) 839-6304