Advances in Hormonal Contraception

Olalekan Dare Olufemi Aworinde

Outline
` ` ` ` `

Introduction Types Advances Summary statement Conclusion

INTRODUCTION The introduction of Enovid, a hormonal contraceptive in 1960, was the most significant event in womens reproductive health in the 21st century. As with all pharmaceuticals, this therapeutic innovation came with a price.
M. E. Flynn

The possibility of inhibiting ovulation was first mentioned by the Austrian physiologist Haberlandt in his book hormonal sterilization in 1921. Ovaries from pregnant does were transplanted into non pregnant rabbits, rendering them infertile for several months In 1927, Haberlandt collaborated with a pharmaceutical firm in Budapest to produce a preparation called Infecundin.

1952 - Colton and Djerassi independently synthesized substances with progesterone - like activity 1956 - Rock J et al demonstrated that norethynodrel suppressed ovulation 1959 - Rock et al conducted large clinical trials using the first COC containing 9.85mg norethynodrel and 150 g mestranol.

This hormonal contraceptive, Enovid was approved for use in the United States in 1960. A variety of hormonal contraceptives are now available with COC the most widely used. Their mechanisms of action include inhibition of ovulation, alteration in cervical mucus, and inhibition of endometrial proliferation thus preventing implantation.

In addition to the contraceptive benefits, many other health benefits have been realized with hormonal contraception ` These include reduction of the risk of endometrial and ovarian cancers, control of menstrual bleeding, and relief from cyclic pelvic pain.
` `

In the evolution of hormonal contraception to its current form, modifications have been made in an effort to decrease side effects and improve effectiveness and compliance and to extend the time on active pills beyond 21 days.

The first change was a decrease in the dose of estrogen and progestin, which led to the low-dose formulations used today Subsequently, new progestins were developed to decrease androgenic side effects. More recently, alternative delivery systems have been introduced in an effort to improve tolerability, compliance, and convenience; these delivery systems include transdermal, vaginal, implantable, and injectable systems.

Types of hormonal contraception

`

Oral contraceptive pills

` `

Progestogen only Combined oral contraceptive pills Progestogen only Combined injectables

Injectables
` `

Implants- biodegradable and non biodegradable ` Patches and vaginal rings ` Hormone impregnated IUDs
`

ORAL CONTRACEPTIVE PILLS

Trends
` ` ` ` `

Lower doses of estrogens Newer progestins Chewable tablets Fewer hormone free days Longer cycles (or no cycles)

Oral contraceptive agents have been modified over time to decrease the side effects especially cardiovascular and androgenic effects and to improve efficacy. This led to:

1.Reduction in dosage of estrogen and progestin. 2.Formation of fixed dosage and phasic pills 3.Introduction of newer progestins with less androgenic effect.

 When

compared with a 35 g EE OC, the 20 g EE OC has comparable cycle control and reduced symptoms of bloating and breast tenderness.

 Both

have less cardiovascular risk (thromboembolism, stroke and heart attack) than the 50 g estrogen COC. pills are either biphasic or triphasic with different doses of estrogen & progestogen in an attempt to mimic the menstrual cycle. to reduce breakthrough bleeding & amenorrhoea with minimal metabolic effects.

 Phasic

 Meant

1st

generation pills COC containing 50 g or more of estrogen. generation pills contain <50 g of estrogen + levonorgestrel, norethisterone, norgestimate generation pills contain progestins such as desogestrel or gestodene

2nd

3rd

Progestins
 The

original progestins used in hormonal contraceptives were all derived from ethisterone, an orally active testosterone derivative. of the carbon at the C-19 position confers progestational activity, with some residual androgenic activity. gonanes were designed to minimize androgenic side effects such as acne, hirsutism, nausea, and lipid changes while increasing progestational effects.

 Removal

 The

A monophasic COC launched in April 2002 Drospirenone, is an analog of the aldosterone antagonist spironolactone that exhibits both progestational and antiandrogenic activity. Contains 30 g of EE and 3mg of drospirenone Has anti-mineralocortocoid activity hence less fluid related weight gain than other combined OCPs Less incidence of acne

Yaz 24/4
`

Same ingredients as Yasmin but

` ` `

EE 20 g (instead of 30 g) 3 mg of drospirenone 24 days of active medication and 4 days of placebo (as compared to the usual 21/7) Has an FDA indication for premenstrual dysphoric disorder (the only hormonal contraceptive with this) Shorter periods

Advantage:
` `

Loestrin 24 Fe ` 24 days of hormones (similar to Yaz 24/4) ` EE 20 g, Norethindrone 1 mg ` Placebo pills contain iron
`

Advantage: ` Periods last less than 3 days ` More pronounced suppression of follicular development

Femcon Fe Chewable spearmint flavored tablet ` EE 35 g, norethindrone 0.4 mg (21 days) ` Placebo contains 75 mg ferrous fumarate
` `

Advantage: For those who cannot swallow pills (and need fresh breath)

Qlaira; Bayer AG
`

A new preparation containing 17-beta-oestradiol a natural oestradiol and dienogest in a multiphasic regime that is optimised to provide good efficacy and at the same time satisfactory cycle control. It is the first preparation using a natural oestradiol, but clinical benefits over the older preparations remain to be explored in comparative studies.

Management of missed COCPs

Seasonale
`

Continuous-use oral Contraceptives Contains 150ug of progestin levonorgestrel & 30 g of estrogen ethinyl estradiol A pill is taken everyday for 84days and 7days free pil Reduction in the in the SE associated with hormone withdrawal period such as: headaches, mood changes Seasonique: Uses the same dose as Seasonale but contains a 0.01 mg dose of estrogen in place of the placebo.

Lybrel
`

(Wyeth Pharmaceuticals)

A 1-year continuous extended OC regimen containing 20 g EE/0.09 mg levonorgestrel Safety and side-effect profiles appear to be similar to those of traditional 21-day cyclic OCs. Ninety-nine percent of women resume ovulation within 3 months after discontinuing the medication.

Multiphasic COC

Comparable in efficacy to monophasic pills It was introduced with an aim of reducing the total dose of hormones per cycle. But no clinically significant difference in adverse effects & continuation rates were found.
Type TriphasicTriquilar Estrogen EE 30 ug (D1-6) EE 40 ug (D7-11) EE 30 ug (D12-21) Progesterone Levonorgestrel 50 ug Levonorgestrel 75 ug Levonorgestrel 125 ug

Progestogen only pills

`

Developed in 1970 in response to reports on estrogen and thromboembolic disease Good option for breast feeding women Unlike COCs they do not reduce milk flow Each progestin only tablet contains: 0.3mg to 0.6mg of norethindrone or 0.03mg to 0.0375mg of levonorgestrel

` ` `

Progestogen only pills

`

They are taken continuously with no hormone free interval between cycle POPs only have a 3hour window to remember that days pill Failure rate 0.3-4/100 women

Cerazette
`

Desogestrel is the progestin in the new progestin only pill developed by Organon Contains 75 g dose It works primarily by preventing ovulation Can be taken as late as 12hours without reducing effectiveness Effectiveness 0.2pregnancies /100 women

` ` `

INJECTABLES

Progestogen only Injectables

`

Highly effective, safe, long lasting & reversible agents for fertility regulation However the continuation rates with these agents are unsatisfactory menstrual irregularities being the most frequent reason for discontinuation

Depo Provera
` ` ` `

150mg Depot medroxyprogesterone acetate Licensed for use in 1992(USA) 1995 (UK) Administered every 12weeks IM Long term Depo-Provera users have low serum estradiol levels which may have an adverse effect on bone mineral density Pregnancy rate 0.3/100women years of use

Noristerat
` ` ` `

200mg norethindrone oenanthate Administered every 8weeks IM Has less effect on bleeding pattern than DMPA Failure rate 0.4/100 women years of use

Depo-subQ Provera 104

`

Contains 104 mg of medroxyprogesterone acetate in a pre-filled syringe with a 0.65 mL volume. Administered subcutaneously 12 to 14 weeks Depo-subQ Provera provides similar contraceptive efficacy to that of Depo provera. Allows self-administration by the user.

Thebleeding pattern for the subQ formation is similar to that of the IM formulation. Return to ovulation after discontinuing deposubQ Provera is longer than that of daily hormonal contraception, with the median time to ovulation after last injection being 10 months. The earliest return of ovulation is 6 months. 20% of women do not resume ovulation within 12 months.

COMBINED INJECTABLES
`

Addition of a short acting estrogen into progestin preparations results in an improvement of endometrial bleeding pattern Allows for early return to ovulation after discontinuation. More than 50% of women become pregnant within six months of discontinuing CICs and 80% within one year.

Combined monthly injectables

`

Cyclofem: 25mg MPA & 15mg oestradiol cypionate (Also known as cyclo-provera, Novafem Lunella)

Mesigyna: 50mg NET EN & 5mg oestradiol valerate (Also known as Norigynon)

Lunelle: 25mg MPA & 5mg oestradiol cypionate

IMPLANTS

Observation that steroid hormones are released at a constant rate from silicone rubber for a long period of time led to the development of subdermal implants for contraception in human by the Population Council in 1966 Synthetic polymers (silastic capsules) containing progestogens were developed to provide sustained release of contraceptive steroids for prolonged use and are implanted subcutaneously or subdermally.

NORPLANTR
6 capsules Progestin- Levonorgestrel (36mg in each capsule) Duration of action: 5years Inserted inside inner aspect of the upper arm above the elbow. efficacy 1st year rates 0.2% and cumulative 5-year pregnancy rate 3.9% side effects are time dependent with the rate declining by about 50% after 1 year Withdrawn from US market in 2002

Major shortcoming is menstrual disorders leading to about half of all discontinuations. No delay in restoration of fertility New research on contraceptive implants has focused on reducing the number to make insertion and removal easier and of less discomfort to clients Newer developments in implantable contraception are focusing on fewer implant rods and less androgenic progestins

Norplant II: Jadelle Two rods containing 75mg each of Levonorgestrel embedded homogeneously within the silastic rods which are covered with a thin sheath of plain silastic. Inserted subdermally Duration of action is 5years Contraceptive protection is similar to Norplant

Uniplant
`

Single rod implant system that consists of 55mg of normogestrel acetate in a capsule that is 3.5cm long and 2.4mm in diameter Duration of action: 1year Menstrual irregularities similar to Norplant

Implanon
` `

Simple 30 mm single silastic rod released 2006 Contains 68mg of etonogestrel (3 keto desogestrel) released at a rate of 30ug/day Duration of action is 3years Apart form its effect on cervical mucus, it also inhibits ovulation better than levonorgestrel Mean insertion time 1.3 minutes (range 1-15 minutes) Mean removal time 3.8 minutes (range 1-60 minutes) 4 cm long and 2 mm in diameter

` `

` ` `

BIODEGRADABLE IMPLANTS

Do not require removal: (i) Capronor: single 40mm rod, levonorgestrel; 1 yr (ii) Capronor II (iii) Capronor III (iv) Annuelle - 90% Norethindrone +10%Cholesterol They have however failed to succeed the nonbiodegradable implants.

VAGINAL RINGS

VAGINAL CONTRACEPTIVE RINGS

Method of long-term contraception which is entirely under patients control. 54mm in diameter Steroids absorbed efficiently thru vaginal epithelium. not coitus related no daily administration

TYPES OF VAGINAL CONTRACEPTIVE RINGS

(a) Progestogen only (i) Levonogestrel - continuos low dose (ii) Progesterone - 90 days use Natural Prolongs lactational amenorrhoea Ineffective during weaning (iii) ST 1435 (Nestrone) - 3 weeks in 1week out. less metabolic effects. (b) Combination rings (i) Levonogestrel/Ethinyl Estradiol (ii) 3 Keto-Desogestrel/EE (iii) Norethindrone Acetate/EE (iv) ST 1435/EE

NuvaRing
`

Releases 120 g of progestin etonogestrel and 15 g of EE/day Left in vagina for three weeks. Removed for one week Can be re-inserted if it has been out for <3hours 8/10 partners do not feel the ring during intercourse A new NuvaRing is needed for each four week cycle Effectiveness: 1.2 pregnancies per 100women

` ` `

Progering
`

Progestin-Only Ring: Contains natural progesterone Releases 10mg of progesterone daily and lasts for 3months Effective at preventing pregnancy among lactating mothers

Vaginal Contraceptive Pill (VCP)

Recent - Undergoing multicentre trials - Historical evolution from vaginal rings

TRANSDERMAL PATCHES

Transdermal Patches ` Works by slow release of combination of progestin and estrogen through the skin
` ` `

Patch; combined preparation Combined patches e.g Ortho Evra It delivers 150 g of the progestin norelgestromin and 20 g of estrogen ethinyl estradiol per day

Design ` Square patch- 4.45cm, different colours (20cm2) ` 3 layers; outer protective polyester layer, middle medicated adhesive layer and a clear polyesterremovable ` Delivers hormones thru skin ` Placed on any part of body ` Adheres to skin: normal activity even bathing ` Reduce adhesion: creams, oils powder, makeup. ` As effective as COC. Better compliance ` Experimental patch: 3.16 cm release 50ug gestodene and 18ug of EE/day.

SPRAY ON CONTRACEPTIVES
`

RESEARCH: PROGESTIN (nestorolone); spray and gel on skin Given daily: dries fast and immediately absorbed: suppresses ovulation

INTRAUTERINE SYSTEMS

Progestin releasing IUS

`

MIRENA (Levonova): ` Introduced in 1990 Delivers levonorgestrel 20ug/day: use for 5 yrs ` As effective as sterilisation
` `

Preg: 0.1 0.2 per 100 women in 1yr. ` In 5yrs : 0.51.1

Causes less bleeding than Copper bearing IUCDs Can be used to treat heavy menstrual bleeding or painful menstrual cramps May be a useful alternative to hysterectomy for some women

EMERGENCY CONTRACEPTION

Therapy used to prevent pregnancy after an unprotected or inadequately protected act of sexual intercourse.
ACOG practice bulletin no 69, obstet gynecol.2005;106: 1443-51

Indications: When no contraceptive has been used ` Contraceptive failure ` Condom breakage, slippage, incorrect use ` 2 or more consecutive missed COC pills ` Late taking of minipills ` More than 2weeks late for progestin-only injectable contraceptive ` More than 7days late for a combined estrogen& progestin monthly injection ` IUCD expulsion ` Sexual assault while not on contraception

Hormonal
`

Levonorgestrel- only regimen: 1.5mg in a single dose or in two doses of 0.75mg taken up to 12hours apart Combined estrogen-progestin (Yuzpe) regimen: two doses of 100mcg ethinyl estradiol & 0.5mg of levonorgestrel taken 12hours apart

Effectiveness: ` Levonorgestrel regimen: 60-93% ` Combined regimen: 56-89%

New research indicates that ECPs can prevent pregnancy up to five days (120hours) after unprotected intercourse against the previous 72 hours timing

Mode of action: ` Prevent and delay ovulation ` Impair endometrial receptivity to implantation of fertilized egg ` Interference with sperm transport and corpus luteum function

The effectiveness of the single-dose regime (LNG 1.5 mg) is similar to that of split-dose LNG Could minimize compliance problems Its currently the recommended regime approved for use up to 72 hours following unprotected sexual intercourse

Mifepristone
`

Progesterone receptor antagonists/modulators can also be used for EC. Mifepristone is superior to LNG in efficacy Doses of 25-50 mg are very effective, and lower doses (less than 25 mg) may be equally good. Menstrual delay is common with mifepristone.

Ulipristal acetate ` a selective progesterone receptor modulator

`

One 30mg dose should be taken as soon as possible, but no later than 120 hours after, unprotected intercourse. Randomised controlled trials show that it is more effective than LNG (failure rate 1.4% versus 2.2%) Women on COC should use barrier method until the next menses bcos it affects P4 metabolism.

MALE HORMONAL CONTRACEPTION

Male reproductive cycle

Still in the trial phase with four major groups ` Aim is to achieve azoospermia although studies have shown that <1million/ml is functionally sterile. ` 99% effective ` 5-20% are non responders Androgen only ` Blocks the production of natural T by giving a dose of synthetic T higher than normally found circulating in the blood. ` The synthetic T suppresses the production of GnRH and LH. ` Synthetic T in the blood cannot cross into the testes, keeping levels of T there too low for sperm production.

Progestin with androgen replacement

`

Blocks the production of the gonadotropins FSH and LH using a synthetic progestin. Lack of FSH and LH blocks the production of spermatids and T in the testes. T is given as replacement therapy to maintain male secondary sex characteristics.

` `

GnRH antagonist with androgen replacement

`

Blocks the action of GnRH. Lack of GnRH stops FSH and LH production, and consequently the production of spermatids and T in the testes. T is given as replacement therapy to maintain male secondary sex characteristics.

Androgen and progestin receptor modulators

`

Slow sperm production by changing the shape of the molecular receptors that bind androgen and progestin so that the male reproductive cells will not correctly produce sperm.

MENT Ac implants
`

MENT Ac (trestolone acetate) methylnortestosterone, is an anabolic steroid which is a derivative of the hormone nandrolone. Promising method for sustained suppression of gonadotrophins and spermatogenesis. can be effective for at least one year. After initial suppression of spermatogenesis, the dose required is lower for continued suppression. Dose-finding and efficacy/safety studies are on

` `

CONTRACEPTIVE VACCINES


Research has been on for a few decades

TYPES A: ANTI-PERIMPLANTATION VACCINE - B-hCG B: HETEROSPECIES DIMER VACCINE - HSD C: CTP VACCINE - 37 AA Carboxyl terminal peptide of BhCG (Linked to Diphtheria Toxoid as Carrier) D: LH-RH VACCINES E:OTHERS: -Anti-Sperm -Anti-Ovum -Anti-Zona Pellucida - Recombinant Zona Pellucida Antigens F: MALE VACCINES -Passive/Active Immunisation against FSH -Gn-RH Vaccine

SUMMARY STATEMENTS

Estrogens in OCPs 2004 Cochrane review ` Low-dose estrogen OCPs resulted in higher rates of bleeding pattern disruptions ` Safety or effectiveness at preventing pregnancy could not be assessed ` Differences in progestin types not accounted for.
`

Gallo MF, Nanda K, Grimes DA, Schulz KF. 20 mcg versus > 20 mcg Estrogen Combined oral contraceptives for contraception. Cochrane Database

Monophasics vs. Biphasics vs. Triphasics

`

There is insufficient data that biphasic or triphasic combined oral contraceptive pills are better than monophasic pills (effectiveness, bleeding patterns, or discontinuation rates) Therefore, monophasic pills are recommended as first choice for women starting OC use. Large, high-quality RCTs that compare triphasic and monophasic OCs with identical progestogens are needed to determine whether triphasic pills differ from monophasic OCs.
Cochrane Database of Systematic Reviews 2007 Van Vliet HAAM, Grimes DA, Lopez LM, Schulz KF, Helmerhorst FM. Triphasic versus monophasic oral contraceptives for contraception Van Vliet HAAM, Grimes DA, Helmerhorst FM, Schulz KF. Biphasic versus monophasic oral contraceptives for contraception

Extended Cycle Contraceptives

`

Seasonale, Seasonique, Lybrel Oral contraceptives taken continuously for more than 28 days compare favorably to traditional cyclic oral contraceptives (bleeding, discontinuation rates, and reported satisfaction)

Edelman AB, Gallo MF, Jense JT, Nichols MD, Schulz KF, Grimes DA. Continuous Or extended cycle versus cyclic use of combined oral contraceptives for contraception. The Cochrane Database of Systematic Reviews 2007 Issue 2

Emergency Contraception
`

Levonorgestrel (LNG) emergency contraception (EC): ` Has little or no effect on post-ovulation events (i.e. fertilization, implantation) ` In rare circumstances EC may prevent implantation but by a similar mechanism as OCPs ` Does not increase risk to an established pregnancy or developing embryo
Novikova N et al. Effectiveness of levonorgestrel emergency contraception given before or after ovulation a pilot study. Contraception 2007:75:112-18.

Emergency Contraception
`

LNG-EC is more effective and is associated with less nausea and vomiting than estrogen-progestin regimens (1.1% vs 3.2%) LNG-EC can be taken as a single dose The two doses of LNG-EC are equally effective if taken 12-24 hours apart
Emergency contraception.ACOG Practice Bulletin No. 69. American College of Obstetricians and Gynecologists. Obstet Gynecol 2005: 106:1443-52.

Emergency contraception
`

Mifepristone middle dose (25-50 mg) was superior to other hormonal regimens. Mifepristone low dose (<25 mg) could be more effective than levonorgestrel 0.75 mg (two doses) but this was not conclusive. Levonorgestrel proved more effective than the Yuzpe regimen.

Steroid hormones for contraception in men

No male hormonal contraceptive is ready for clinical use. ` Most trials were small exploratory studies. Their power to detect important differences was limited and their results imprecise. ` In addition, assessment of azoospermia can vary by sensitivity of the method used. ` Future trials need more attention to the methodological requirements for RCTs. ` More trials with adequate power would also be helpful
`

Extended cycle vs. cyclic use of combined hormonal contraceptives ` Evidence from existing randomized control trials comparing CHCs given continuously (greater than 28 days of active combined hormones) to traditional monthly cyclic dosing (21 days of active hormone and 7 days of placebo) is of good quality.
`

However, the variations in type of hormones and time length for continuous dosing make a formal meta-analysis impossible. More attention needs to be directed towards participant satisfaction and menstruation-associated symptoms.

Progestogen-releasing IUS vs other forms of reversible contraceptives ` Evidence suggests there is no difference in pregnancy rates among LNG-20 IUS and Norplant-2 users. ` Continuation rates for LNG-20 IUS& Norplant2 were similar. ` Lack of menstrual bleeding was the main reason for discontinuation of LNG-20 IUS. ` LNG-20 IUS does not affect breastfeeding or the growth and devpt of lactating breastfed infants. ` The device did not have an adverse effect on glucose metabolism among IDDM women.

CONCLUSION
have been altering formulations and delivery systems for hormonal contraceptives used by more than 100 million women worldwide to develop new versions that are safer, more acceptable, and easier to use. products are now entering the market, some only in the developed world but some also in developing countries. hope more choices will result in greater method acceptability, client satisfaction, consistent use, continuation, and ultimately fewer unplanned pregnancies."
We New Researchers

LOCAL EXPERIENCE
Available hormonal contraceptives in IHU ` COC ` POP ` Injectables- Depo Provera and Noristerat ` Implanon % uptake in last 12months= 27.65% of contraceptives Injectables (10.6%)being most used and POP (2.3%) least used.

April 2010- April 2011 review

Month April 10 May 10 June 10 July 10 Aug 10 Sept 10 Oct 10 Nov 10 Dec 10 Jan 10 Feb 10 Mar 10 April 10 Total Injectables 2 1 0 4 0 3 0 3 3 2 0 4 1 23 COC 1 3 3 2 1 0 3 0 1 2 0 0 1 17 POP 0 0 0 1 0 0 0 1 0 2 0 0 1 5 Implanon 0 1 0 2 0 3 0 0 2 1 3 2 1 15 Non hormonal 13 14 17 21 2 10 15 9 0 16 9 15 16 157 Total 16 19 20 30 3 16 18 13 6 23 12 21 20 217

THANK YOU!