Hormonal Advances Olufemi

8/6/2019 Hormonal Advances Olufemi

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Advances in Hormonal

Contraception

Olalekan Dare

Olufemi Aworinde


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Outline

` Introduction

` Types

` Advances

` Summary statement

` Conclusion


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INTRODUCTION

The introduction of Enovid, a hormonal

contraceptive in 1960, was the most significant

event in womens reproductive health in the21st century. As with all pharmaceuticals, this

therapeutic innovation came with a price.

M. E. Flynn


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` 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 forseveral months

` In 1927, Haberlandt collaborated with apharmaceutical firm in Budapest to produce a

preparation called Infecundin.


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` 1952 - Colton and Djerassi independently

synthesized substances with progesterone - likeactivity

` 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 150g mestranol.


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` 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.


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` 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.


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Types of hormonal contraception

` Oral contraceptive pills` Progestogen only

` Combined oral contraceptive pills

`

Injectables` Progestogen only

` Combined injectables

` Implants- biodegradable and non biodegradable

` Patches and vaginal rings

` Hormone impregnated IUDs


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ORAL CONTRACEPTIVE PILLS


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Trends

` Lower doses of estrogens

` Newer progestins

` Chewable tablets

`

Fewer hormone free days

` Longer cycles (or no cycles)


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` Oral contraceptive agents have been modified over

time to decrease the side effects especially

cardiovascular and androgenic effects and toimprove 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.


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When compared with a 35g EE OC, the 20g 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.

Phasic pills are either biphasic or triphasic with different

doses of estrogen & progestogen in an attempt to

mimic the menstrual cycle.

Meant to reduce breakthrough bleeding & amenorrhoea

with minimal metabolic effects.


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1st generation pills COC containing 50 g ormore of estrogen.

2nd generation pills contain


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The original progestins used in hormonal contraceptiveswere all derived from ethisterone, an orally activetestosterone derivative.

Removal of the carbon at the C-19 position confersprogestational activity, with some residual androgenicactivity.

The gonanes were designed to minimize androgenicside effects such as acne, hirsutism, nausea, and lipidchanges while increasing progestational effects.

Progestins


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` A monophasic COC launched in April 2002

` Drospirenone, is an analog of the aldosteroneantagonist spironolactone that exhibits both

progestational and antiandrogenic activity.

` Contains 30 g of EE and 3mg of drospirenone

`

Has anti-mineralocortocoid activity hence less fluidrelated weight gain than other combined OCPs

` L

ess incidence of acne


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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 (ascompared to the usual 21/7)

` Advantage:

` Has an FDA indication for premenstrual dysphoric

disorder (the only hormonal contraceptive with this)

` Shorter periods


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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


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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)


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Qlaira; Bayer AG

` A new preparation containing 17-beta-oestradiol anatural 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 preparationsremain to be explored in comparative studies.


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Management ofmissed COCPs


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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.


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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 adverseeffects & continuation rates were found.

Type Estrogen ProgesteroneTriphasic-

Triquilar

EE 30 ug (D1-6)

EE 40 ug (D7-11)

EE 30 ug (D12-21)

Levonorgestrel 50 ug




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Progestogen only pills

` Developed in 1970 in response to reports onestrogen 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 0.6mgof norethindrone or 0.03mg to 0.0375mg oflevonorgestrel


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Progestogen onlypills

` They are taken continuously with no hormone freeinterval between cycle

` POPs only have a 3hour window to remember thatdays pill

`

Failure rate 0.3-4/100 women


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INJECTABLES


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Progestogen only Injectables

` Highly effective, safe, long lasting & reversible agentsfor fertility regulation

` However the continuation rates with these agentsare unsatisfactory

` menstrual irregularities being the most frequentreason for discontinuation


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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 serumestradiol levels which may have an adverse effect onbone mineral density

` Pregnancy rate 0.3/100women years of use


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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


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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.


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COMBINED INJECTABLES

` Addition of a short acting estrogen into progestinpreparations 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.


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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


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IMPLANTS


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` Observation that steroid hormones are released ata constant rate from silicone rubber for a long

period of time led to the development of subdermalimplants for contraception in human by thePopulation Council in 1966

` Synthetic polymers (silastic capsules) containingprogestogens were developed to provide sustainedrelease of contraceptive steroids for prolonged useand are implanted subcutaneously or subdermally.


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NORPLANTR

6 capsules Progestin- Levonorgestrel (36mg in each capsule)

Duration of action: 5years

Inserted inside inner aspect of the upper armabove 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

M j h i i l di d l di


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Major shortcoming is menstrual disorders leading toabout half of all discontinuations.

No delay in restoration of fertility

New research on contraceptive implants has focusedon reducing the number to make insertion andremoval easier and of less discomfort to clients

Newer developments in implantable contraceptionare focusing on fewer implant rods and lessandrogenic progestins


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Norplant II: Jadelle

Two rods containing 75mg each ofLevonorgestrelembedded 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


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Uniplant

` Single rod implant system that consists of 55mg ofnormogestrel acetate in a capsule that is 3.5cm

long and 2.4mm in diameter

` Duration of action: 1year

` Menstrual irregularities similar to Norplant


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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


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VAGINAL RINGS


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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


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TYPES OF VAGINALCONTRACEPTIVE 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) NorethindroneAcetate/EE

(iv) ST 1435/EE

N Ri


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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


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Progering

` Progestin-Only Ring: Contains natural progesterone

` Releases 10mg of progesterone daily and lasts for

3months

` Effective at preventing pregnancy among lactating

mothers


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Vaginal Contraceptive Pill (VCP)

Recent

- Undergoing multicentre trials

- Historical evolution from vaginal rings


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TRANSDERMAL PATCHES


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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 norelgestrominand 20 g of estrogen ethinyl estradiol per day


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Design

` Square patch- 4.45cm, different colours (20cm2)

` 3 layers; outer protective polyester layer, middlemedicated adhesive layer and a clear polyester-removable

`

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 gestodeneand 18ug of EE/day.


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SPRAY ON CONTRACEPTIVES

` RESEARCH: PROGESTIN (nestorolone); spray andgel on skin

` Given daily: dries fast and immediately absorbed:suppresses ovulation


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INTRAUTERINE SYSTEMS


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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


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EMERGENCY CONTRACEPTION

Therapy used to prevent pregnancy after an unprotected orinadequately protected act of sexual intercourse.

ACOG practice bulletin no 69, obstet gynecol.2005;106: 1443-51


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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


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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%


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` New research indicates that ECPs can preventpregnancy up to five days (120hours) after

unprotected intercourse against the previous 72hours timing

Mode of action:

` Prevent and delay ovulation

` Impair endometrial receptivity to implantation offertilized egg

` Interference with sperm transport and corpusluteum function


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` The effectiveness of the single-dose regime (LNG1.5 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 unprotectedsexual intercourse


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Mifepristone

` Progesterone receptor antagonists/modulators canalso 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.


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MALE

HORMONAL

CONTRACEPTION


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Still in the trial phase with four major groups


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p j g p` Aim is to achieve azoospermia although studies have

shown that


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Progestin with androgen replacement

` Blocks the production of the gonadotropins FSHand LH using a synthetic progestin.

` Lack of FSH and

LH blocks the production ofspermatids and T in the testes.

` T is given as replacement therapy to maintain male

secondary sex characteristics.

`

GnRH antagonist with androgen replacement


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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 inthe testes.

` T is given as replacement therapy to maintain male

secondary sex characteristics.

Androgen and progestin receptor modulators


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Androgenand progestin receptor modulators

`

Slow sperm production by changing the shapeof the molecular receptors that bind androgen

and progestin so that the male reproductive

cells will not correctly produce sperm.


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CONTRACEPTIVE VACCINES


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CONTRACEPTIVE VACCINES Research has been on for a few decades

TYPESA: 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


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SUMMARY STATEMENTS


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h i i h i T i h i


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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 andmonophasic OCs with identical progestogens are needed to

determine whether triphasic pills differ from monophasicOCs.

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


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EmergencyContraception

` 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.


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EmergencyContraception

` LNG-EC is more effective and is associated with lessnausea and vomiting than estrogen-progestin

regimens (1.1% vs 3.2%)

` LNG-EC can be taken as a single dose

`

The two doses ofLNG-EC are equally effective iftaken 12-24 hours apart

Emergency contraception. ACOG Practice Bulletin No. 69. American College of

Obstetricians and G necolo ists. Obstet G necol 2005: 106:1443-52.


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Emergency contraception

` Mifepristone middle dose (25-50 mg) was superiorto other hormonal regimens.

` Mifepristone low dose (


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Extendedcycle vs.cyclicuse ofcombined


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y y

hormonalcontraceptives

` Evidence from existing randomized control trials comparing

CHCs given continuously (greater than 28 days of activecombined 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.


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CONCLUSION

Researchers have been altering formulations and deliverysystems for hormonal contraceptives used by more than

100 million women worldwide to develop new versions

that are safer, more acceptable, and easier to use.

New products are now entering the market, some only in

the developed world but some also in developing countries.

We hope more choices will result in greater methodacceptability, client satisfaction, consistent use, continuation,

and ultimately fewer unplanned pregnancies."

LOCAL EXPERIENCE


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LOCALEXPERIENCE

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


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p pMonth Injectables COC POP Implanon Non hormonal Total

April 10 2 1 0 0 13 16

May 10 1 3 0 1 14 19

June 10 0 3 0 0 17 20

July 10 4 2 1 2 21 30

Aug 10 0 1 0 0 2 3

Sept 10 3 0 0 3 10 16

Oct 10 0 3 0 0 15 18

Nov 10 3 0 1 0 9 13

Dec 10 3 1 0 2 0 6

Jan 10 2 2 2 1 16 23

Feb 10 0 0 0 3 9 12

Mar 10 4 0 0 2 15 21

April 10 1 1 1 1 16 20

Total 23 17 5 15 157 217


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THANK YOU!

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