Recent Developments in ContraceptivesDr.M.M.MisroDepartment of Reproductive Biomedicine

IntroductionThe contraceptive burden is mostly on women.Family planning services are mostly female centric.This is because of the availability of a few variety of contraceptive choices to women.An effective male contraceptive is still yet to be available.

Current male methods:Vasectomy/male sterilizationIt is the surgical and terminal method.Principal method since 1960sHigh efficacy (1-2 failures/1000 proced.)Complications include: Haematoma or infection in 5 %, recanalization in 3 % and granuloma from 3-75 % with no mortality.Rise in sperm antibody titer with time.Reversal not easy/requires microsurgery

CondomsIt is the barrier method of contraception.In recent times it is also advocated as a method protecting STDs.It has poor user compliance and high failure rate.Mostly made out of latex but recently poly urethane material has been used which provide higher tensile strength.

Experimental approaches (male)-Hormonal-Poor understanding of the complex intra-testicular regulatory mechanisms makes it difficult to target pathways leading to disruption of spermatogenesis.The most realistic way is to suppress gonadotropins there by abrogating leydig cell steroidogenesis and nullifying FSH simultaneously.

Experimental approaches (male)-Hormonal-Selective suppression of FSH is not a viable approach to achieve azoospermia. Active or passive immunization against FSH produced modest suppression of spermatogenesis. Mutations in FSH receptor gene or in FSH beta knock out mice, spermatogenesis is only moderately impaired.

Experimental approaches (male)-Hormonal-Exogenously administered sex steroids are the most likely candidate for suppression of gonadotropins and spermatogenesis.Androgens alone or progestogens combined with androgens were indeed effective in suppressing spermatogenesis

Androgens aloneIt was chosen because of the well documented safety of T in many years of clinical use in hypogonadal men.It is economical and acceptable since as a single agent it can achieve both gonadotropin, spermatogenesis suppression and maintain sexual function simultaneously.

Testosterone enanthateTE injection was the form of contraception used 200 mg weekly.Tested in 10 centres in 7 countries involving 271 volunteers.157 men became azoospermic, in the 12 month efficacy phase, one pregnancy occurred out of 1486 months of exposure.Efficacy comparable with female contraceptive.

Testosterone enanthateHowever, a substantial minority of men remained oligospermic despite suppression of gonadotropins to undetectable levels.The incidence of side effects like acne (29.3 %), weight gain, changes in sex drive and mood was low.HDL cholesterol and total cholesterol decreased by 18 % and 6 % respectively while haematocrit increased by 6 %.

Testosterone ImplantsSurgical implantation of T pellets was tried subcutaneously.At 600 to 800 mg, relatively stable levels of hormone can be maintained for 4-76 months.Efficacy similar to TE but side effects are less.Extrusion of T pellets occurred in some cases.

Testosterone undecanoateIt is testosterone ester with a long aliphatic side chain that increases its lipid solubility and facilitates absorption into intestinal lymphatics.A single dose of 1000 mg T undecanoate has a half life of 33.9 days in hypogonadal men compared with 4.5 days for 250 mg of T enathate.TU (1000) induced azoospermia in all 12 subjects in China, while 11 out of 12 achieved the same even with 500 mg.

Testosterone BuciclateT-17-trans-4-butyl-cyclohexylcarboxylateLong acting ester jointly developed by WHO and NICHD, USA600-1000 mg in single dose injections maintain stable concentrations for 16-20 weeks.1200 mg of TB induced azoospermia in 3 out of 8 eugonadal men with plasma testo. with in normal physiological range.

MENT7-Methyl-19-nortestosterone.It is four times more potent than T in maintaining prostate and seminal vesicle wts.But 10 to 12 times more potent in suppressing gonadotropins.10 times more potent than T in decreasing HDL and total cholesterol.It has the potential advantage of being used at a low dose (1/10 of T) to suppress gonadotropins.

MENT(7-methyl 19-nortestosterone)Lower doses may also permit sufficient drug to be delivered by subdermal implants, skin patches or gels.Single injection of 2-8 mg of micronized MENT to healthy men suppressed gonadotropins with out any side effects.Subcutaneous implants 115 mg was found to maintain sexual behavior and mood in hyogonadal men over a 6 week period.

Combined hormonal male contraceptiveAndrogen related side effects due to supraphysiological T levels are natural with androgen only regimens.There is increased risk of benign prostatic hyperplasia, prostatic carcinoma and cardiovascular disease in later years with behavioural disturbances.Intra-testicular testosterone.Progestin as main antigonadotropic agent and T replacement in lower doses to sustain libido.

DMPA + T enanthateDMPA (200 0r 100 mg) and T enanthate (250 or 100 mg) at monthly intervals for four months suppressed spermatogenesis in 19 out of 20 Indonesian men.Indonesia-5 centres-DMPA combined with MENT (3 weekly) or T enanthate (weekly) was effective-azoosp.-97 % of subjects-after 6 months.

Levonorgestrel + TOral levonorgestrel (500g)/day + T enathate 100 mg/week induced azoospermia in 12 out of 18 men.Reducing the dose of levonorgestrel to 250 or 125 g produced similar results.Oral desogestrel 150-300 g + TE 50-100 mg/week-azoosp. in 18 of 24 men.But it decreased HDL-chlesterol indicating that 19 NT derived progestogens can effect lipid metabolism in men independent of T.

CPA + TEIt is synthetic steroid with both progestogenic and anti-androgenic properties.It is used for hirsutism and prostate cancer.12.5-100 mg daily + TE induced azoospermia in all subjects.More clinical trials are needed for dose stand. of diff. combinations/efficacy.

GnRH analogues + androgensSuppression of gonadotropins can also be achieved by blocking GnRH receptors in the gonadotrophs in anterior pituitary.This is achieved by two ways: 1. by continuous administration agonistic analogues of GnRH which down regulates receptors for GnRH. and 2. through administration of GnRH antagonists which would prevent the binding of native GnRH to its receptor.

GnRH agonist + TLong acting depo preparations of GnRH agonists with T have been explored for contraceptive efficacy in 12 clinical studies.Only 23 % subjects-azoospermia.The modest efficacy is further blunted by simultaneous administration of T. Inadequate doses of agonists, cost, persistence of FSH are some of the reasons for its discontinuation as a potential contraceptive.

GnRH antagonists + TGnRH antagonists compete for GnRH receptors along with native GnRH-slower dissociation rate.Induce rapid suppression of gonadotropinsThese along with simultaneous or delayed introduction of T replacement induce azoo. with in 6-8 weeks.Local histamine reaction has been reported with some antagonists.Low half life- daily injection-more costly-presently shelved as a potential contraceptive

A monthly injectable male contraceptive?Yet to be availableResearch is underway in our Institute too.A progestin plus long acting testosterone has been tried-successful in animal trialsContraceptive efficacy is 100 %.Complete arrest of spermatogenesis after 60 days.After 60 days, the frequency of injection could be increased to 45 days or even 2 months.

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.

BIOQUAL's male contraceptive leads: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.

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.

Bioqual team: Dr. Barbara Attardi The work follows on a second androgen ester (11-methyl-19-nortestosterone 17-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 11-methyl-19-nortestosterone 17-dodecylcarbonate in rats and rabbits (similar studies have already been completed for DMAU). DMAU has alsobeen tested at a lower dose in the rabbit antifertility study, and we have initiated testing of 11-methyl-19-nortestosterone 17-dodecylcarbonate for antispermatogenic effects in this model.

Testicular antispermatogenic agentsGossypol, the plant pigment from cotton seed oil was tested as a male contraceptive in 9000 men in China in 70s. It was shown to have good contraceptive efficacy.Irreversible fertility and unacceptable side effects such as hypokalaemia-it is not followed up as a contraceptive any more.Plant product from Tryperigium wilfordi- affects spermatogenesis-reduces sperm motility, good contra. efficacy- but has immunosuppressive side effects.

Post-testicular epididymal agentsThe idea is to affect the sperm maturation processes in the epididymis for induction of contraceptive efficacy.-chlorohydrin and 6-chloro-6-deoxy-glucose have been tried-metabolize to 3-chlorolactaldehyde, which has similar stereochemistry as R-glyceraldehyde, the substrate for the glycolytic enzyme glyceroldehyde 3-phosphatase dehydrogenase.Inhibit oxidative metabolism of glucose and other sugars-induce loss of sperm motility.Adverse effects on nervous system and bone marrow did not support these for further development.

Vas occlusive/nonocclusive agentsDeveloped at IIT/AIIMSA hydrogel/copolymer styrene maleic anhydrideTested in rats/monkeys and clinical studies-phase II/extendedStopped further trials because of concerns of swelling in the testis/granulomaICMR has now given approval for further trials in multiple centres.

Female Contraceptive MethodsFemale sterilizationIUDsVaginal barriers/condomsInjectable/implantsOral contraceptives: OCPs, POPsNonsteroidal contraceptives-SaheliVaginal ringsSubdermal patchesEmergency contraceptives

Saheli (centchroman)Developed by CDRIAnti estrogen30 mg dose to be taken 1st day of menstrual cycleFollowed by 2 and 4th day of week for 3 monthsThen once a week

LNG IUS-progestin carrying IUD by Mirena, Berlex Lab. Montville, USAIt is a small plastic T-shaped device that releases 20 g/day of levonorgestrel.Once in place provides hormonal contraception for 5 years.Reduces menstrual blood loss by more than 80 % at 3 months and 95 % at 12 months compared with control cycles.Reduces menstrual pain

Implanon-hormone releasing implant (Oraganon, Natherlands) Contains progestin etonogestrel, a major metabolite of desogestrel.Provides contraceptive efficacy for 3 yearsThe ethylene vinyl acetate polymer implant is 40 mm long and 2mm in diameter.Release rate of progestin 60 g/day.Approved for use in Indonesia and Europe-failure rate 0.05 %

Lunnelle:The new monthly injectable (Pharmacia Corp.)Approved by FDA in 2000.25 mg of Medrpxy progesterone acetate (MPA) + 5 mg of estrogen cypionateSuppresses ovln.- Failure rate 0.1 % only.Advantages over 3 monthly progestin only injectables include rapid return of fertility after discontinuation & improved bleeding patterns.Yet to be available as a product.

Once a month pill?Only available in China, yet to be approved by FDA or in other countries like India legally.Levonorgestrel (6 mg) and Quinestrel (3 mg)To be initiated on 5th day of cycle, 20 days later the administrn. has to be repeated. This date has to memorized for administrating the drug in the following months.Contraceptive efficacy 98.30 %Side effects include dizziness, nausea and increase of leucorrhoea.

Vaginal ring-(Nuvaring, Organon)Approved by FDA in 2001(fail. Rate 1-2 in 100 women years of use)Contains 120 g etonogestrel and 15 g EEAdvantages-rapid and efficient absorption in veg. epi., user controlled (insertion & removal), provides sustained release of ster. /comb.of ster. Inserted for a 3 wk period and removed for 1 wk during which withdrawal bleeding occurs.It is made of flexible plastic, ethylene vinyl acetate copolymer-approx. 2 inches in dia.

Contraceptive patch-Transdermal delivery of steroids(ortho Evra, US)Releases 150 g/day of norelgestromin (active metabolite of the progestin norgestimate) and 20 g/day of EE.It is 20 cm2 (4.5x 4.5 cm)-applied once a week in the abdomen, buttock, arm or torso)-user controlled.With the use of this, sustained release- up to 9 days- good protection against pregnancy- failure 0.8 %

What is an Emergency Contraceptive? As per WHO definition Emergency contraception refers to a particular type of contraception that is used as an emergency procedure to prevent pregnancy following an unprotected, possibly a fertile intercourse.

Emergency Contraceptive MethodsUnder Dev.DanazolMifepristone

EstablishedHigh dose E2Copper T (IUD)The Yuzpe methodProgestin only pills

Significance of Emergency ContraceptivesUnprotected sexual intercourse 5 days before ovulation: Probability of conception is 10 %Unprotected sexual intercourse on the day of ovulation: Probability of conception is 33 % (Wilcox.1995) Fertile period highly variable (70% ovulate either before day 10 or after day 17 of MC)

Indication of use of ECsFailure of contraceptives methods being used (Condom rapture, diaphragm slippage or forgotten oral pills)Sexual assaultOr following any unprotected sexual act and those who want to avoid pregnancy

EC: Mechanism of action ECs work before implantation: the exact mechanism of action-site of action is difficult to pinpoint.However, more than one mechanism is believed to be involved.The mechanism may vary depending on when EC is used during the menstrual cycle.

EC Methods:High dose Estrogens Tried in early 60s, within 72 hrs after coitusDiethylstibestrol (50 mgs)/day-5daysSubsequently reduced to 0.5-5 mgs of ethynyl estradiol two doses 12 hrs apart for 5 days-as practiced recentlyGood efficacy, pregn. Rate

Emergency contraceptivesDanazolSynthetic progestin with androg. Prop.Dose-400 mg-2-3 doses at 12 hr intervalEffic. > Yuzpe method-mild side effectsLow fail. rate 1.7 %-800 mg 0.8 % 1200 mgAlters endometr. environ. No effect ovuln.Women with contraindic. Ocs- can useExpensive-India specific studies are needed

Emergency contraceptivesMifepristoneSynth. 19 nor steroid deriv. Pot. Anti.prog.600 mg single dose within 72 hrs of expos.25 mg/12 hr- two doses-100 % success rate25 mg single dose-83 % success rateAffects follicl. Maturan. Ovln & Fertlizn.Acclr. Embr. Trans.- Prevn. Impln.Side effects less- more studies are needed.

Emergency contraceptivesCuTInserted post-coitallyWindow period extended to 5-7 daysCan be given to women with E2 contraind.Cannot be give to a nulliparous womenEfficacy high Fail. Rate< 0.1 %Prevents implantation

Emergency contraceptivesYuzpe method

100 g estrogen + 1 mg dl-norgestrelpresent regm. 200 g ethynyl estradiol + 1mg of levonorg. -half first-half 12 hrs laterSame ingrad. As OCs- acceptableEfficacy > 75 % Fail. Rate- 0.2-2 %Stops ovln. Alters endometr. Envirn.Side effects are more.

Emergency contraceptivesProgestin only pillsLevonorgestrel-dedicated regimen0.75 mgs two doses 12 hrs apartEfficacy >80 %, Fail. Rate.< 2%Side effects lessAvailable now in Spl. Packed kits Pill 72 from Cipla

EC: Mechanism of action (Progestin only EC)Affects indicate both follicular growth and dev.of CLGiven in early foll.ph the cycle length is prolonged-Due to increas. duratn. of foll ph. Post treatmnt biopsies show proliferative endometr.Around time of ovl.-varied response-blocks ovul. -in some shows foll.actv but deficient luteal functionGiven in luteal phase-did not affect cycle length or cause any signif. endometrial changes

EC: Mechanism of action

Type of EC

Effect on folli. Growth

Blocks ovuln.

Incr./Decr. in cycle length

Alterns. in endometri./prevent implantn.

Affects

CL func/luteolysis.

Inhibits fertilizn.

Alt. In transp. egg/sperm/emb

Toxic action Egg/sperm/emb

CuT

-

-

-

Yes

-

yes

Yes

yes

Danaz.

Yes

Yes

?

?

?

-

?

RU 486

Yes

Yes

?

Yes

Yes

-

?

?

Yuzpe

Yes

Yes

?

Yes

Yes

-

?

No

LNG

Yes

Yes

?

Yes

Yes

-

?

No

ConclusionCafeteria approach: The emphasis is on research for development of more potent contraceptivesTo be able to provide people with more choices.A contraceptive for the male is yet to come up-efforts are on.More knowledge on molecular aspects in reproductive medicine/reproductive biology is essential for identifying targets for contraceptive intervention.