Contraception through the phases of a woman’s life

Judy Kluge

Dept of Obs and Gynae

University of Stellenbosch

Contraceptive options

Contraceptive effectiveness

• efficacy (theoretical ability to prevent pregnancy)

• compliance

• continuation

• fecundity (ability to conceive)

• timing of coitus.

Efficacy

Source: Trussell J. Contraceptive

Efficacy. In Hatcher RA, Trussell J, Nelson AL, Cates W, Kowal D, Policar M.

Contraceptive Technology: Twentieth Revised Edition. New York NY: Ardent

Media, 2011

LONG ACTING REVERSIBLE CONTRACEPTION / LARCs

Contraceptive CHOICE project

• Prospective cohort study of over 9,000 women, 14-45 yrs– 75% participants chose 1 of 3 LARC methods (46%

LNG-IUS; 12% Cu-IUD, 17% subdermal implant).

• LARC users > continuation than non-LARC users– 12 months (87% versus 57%) – 24 months (77% versus 41%)

• LARCs were 20 X more effective than non-LARC methods.

• Substantial reductions in teen pregnancy, birth, and abortion

Birgisson et al. Preventing unintended pregnancy , The Contraceptive Choice Project in Review. J Womens Health (Larchmt). 2015 May;24(5):349-53

Health Concerns

Health Concerns

BENEFIT

RISK

Family planning

27

WHO Medical Eligibility Criteria For Contraceptive Use. (5th edition,2015 )

Classification of Category Ratings

1 No restriction for the use of the contraceptive method

Use method under any circumstance

2 Advantages of using method generally outweigh theoretical or proven risks

Generally use the method

3 Theoretical or proven risks usually outweigh advantages of using method

Use not usually recommended unless othermore appropriate methods are not available or not acceptable

4 Represents an unacceptable health risk if the contraceptive method is used

Do not use the method

Ideal Contraceptive Method?

• WHO MEC 1 ( & WHO MEC 2)

• Highest tier of efficacy (<1 pregnancy per 100)

• PLUS minimal side effects and maximal non-contraceptive benefits

• for a particular woman might change over time– ↓ need for efficacy with ↓ biologic fertility,

– the emergence of age-related co-morbidities,

– Management of symptoms of co-existing conditions e.g. perimenopause

– the development of new contraceptive technology.

Non contraceptive benefits: Combined Hormonal Contraception

• ↓ Heavy Menstrual Bleeding • E2V/ Dienogest = FDA approved for HMB

• ↓ Fe def. Anaemia

• ↓ dysmenorrhoea (1 & 2)

• ↓ endometrial , ovarian, colorectal cancer

• ↓ ectopic pregnancy

• ↓symptoms of premenstrual dysphoric disorder/ PMDD (only EE/DRSP)

• ↓Pelvic inflammatory disease

Non contraceptive benefits: Combined Hormonal Contraception

• ↓ functional cyst formation (not treatment)

• Rx for endometriosis

• Rx for hyperandrogenism (acne, hirsutism, PCOS)

• Cycle control/Unscheduled bleeding

– CHC better than Progestogen- only

– 30-35µg EE > 20 µg EE

– Combined Vag Ring > COC/patch

Non contraceptive benefits: Progestogen only contraception

• LNG – IUS (Mirena®/ Levosert®)

– HMB and anaemia : At 12 months >90% reduction in blood loss

– ↓endometrial hyperplasia and cancer,

– ↓ reduces rates of endometrial polyps in users of tamoxifen

– ↓ alleviates pain associated with endometriosis &adenomyosis

Non contraceptive benefits: Progestogen only contraception

• Depot medroxyprogesterone acetate / DMPA (Petogen® )

– HMB

– endometriosis.

• Etonogestrel-releasing contraceptive implant (Implanon Nxt®)

– Dysmenorrhoea (70% reduction)

Non contraceptive benefits

• copper intrauterine device

– ↓rates of endometrial and cervical cancer

Which Combined Hormonal contraception?

• Type & dose of Progestogen?

• Type & dose of Oestrogen?

• Regimen? – 21/7

– 24/4

– 26/2

– Extended regimens e.g. 84/7 OR continuous active

• Monophasic/biphasic/triphasic/quadraphasic

• Route: oral/transdermal/ vaginal

Brand name Type of oestrogen Dose (μg) * Type of progestogen Dose (μg)*

Minesse® /Mirelle® Ethinyl oestradiol 15 Gestodene 60

Melodene® Ethinyl oestradiol 20 Gestodene 75

Mercilon® Ethinyl oestradiol 20 Desogestrel 150

Nordette®/ Oralcon® Ethinyl oestradiol 30 Levonorgestrel 150

Femodene® / Minulette® Ethinyl oestradiol 30 Gestodene 75

Marvelon® Ethinyl oestradiol 30 Desogestrel 150

Yasmin® Ethinyl oestradiol 30 Drospirenone 3 g

YAZ® Ethinyl oestradiol 20 Drospirenone 3 g

Triphasil® /Trigestrel®/ Logynon® Ethinyl oestradiol 30/40/30 Levenorgestrel 50/75/125

Tri-Minulet® / Triodene Ethinyl oestradiol 30/40/30 Gestodene 50/70/100

Brevinor® Ethinyl oestradiol 35 Norethisterone 0.5 mg

Dianne 35®/ Ginette®/ Adco-Fem-

35®/ Minerva®

Ethinyl oestradiol 35 Cyiproterone acetate 2 mg

Trinovum® Ethinyl oestradiol 35 Norethisterone 0.5/0.75/1 mg

Biphasil® Ethinyl oestradiol 50 Levonorgestrel 50/125

Ovral® Ethinyl oestradiol 50 Norgestrel 500

Qlaira® Estradiol valerate 3 / 2 / 1 mg Dienogest 2 / 3 mg

ZoelyTM 17 ß Estradiol (E2) 1,5 mg Nomegestrol acetate 2,5 mg

*Unless otherwise stated

OESTROGENS

1. Ethinyloestradiol (EE)– in most COCs

2. Oestradiol Valerate (E2V)

3. 17 β oestradiol (E2)

EE

E2

22

Background Information

E2 Is Rapidly Metabolized1,2

1. Fotherby K. Contraception .1996;54:59–69.

E1EstroneE2

Estradiol Several-fold lower

activity than estradiol

E1SEstrone sulphate

Inactive form

Long-lived derivative and reservoir of E1/E2

Principal active form

High protein binding

Low bioavailability: ~5%

23

Background Information

EE Is Slowly Metabolized1,2

EE

EE

EE

↑ biologic activity vs natural

estrogens

― Ethinyl group inhibits metabolism

― Long half-life

― High bioavailability (45-55%)

1. Lobo RA et al. Am J Obstet Gynecol. 1994;170:1499–1507.

2. Guengerich FP. Life Sci. 1990;47:1981–1988.

EE

EE

EE

EE = ethinyl estradiol

24

Background Information

E2 and EE: Effects on Tissue-Specific

and Systemic Parameters

EE effects are up to 300-600X greater than those of E2 in some tissues1

EE is ~100X more potent on systemic parameters

1. Mashchak CA et al. Am J Obstet Gynecol. 1982;144:511–518.

2. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility, 7th ed., 2005, p. 691.

a Estimated relative potency normalized to E2. The clinical relevance of these measurements is unknown.

EE = ethinyl estradiol; E2 = estradiol; FSH = follicle-stimulating hormone; SHBG = sex hormone-binding globulin; CBG = corticosteroid-binding globulin;

BMD = bone mineral density.

SHBG1 CBG1 Angiotensinogen1 BMD2 FSH1

E2 1 1 1 1 1

EE 614 525 330 200 60–150

1.5 mg E2 oral

dose

2 mg EE 3 mg EE 5 mg EE 8 mg EE 10-25 mg EE

Tissue-Specific Effectsa Systemic Effectsa

≈

Different Progestogens

Royer P & Jones K. CLINICAL OBSTETRICS AND GYNECOLOGY Volume 57, Number 4, 644–658

PROGESTOGENS in COCs

Progestogen Date of introduction

Generation Product

Norethynodrel 1950’s First Enovid

Norethisterone Early 1960’s Second Anovlar

(PrimolutN)

Levonorgestrel Early 1970’s Second Nordette

Biphasil

Norgestimate Late 1980’s Second/third Cilest

Gestodene Mid 1980’s Third Femodene/ Minulette/ Minesse

Desogestrel Mid 1980’s Third Marvelon/ Mercilon

Drosperinone Early 2000 Fourth Yasmin/Yaz

Biological Findings Associated

With Steroid Receptor Agonism

• Progesterone receptor (PR)

– Establish and maintain pregnancy

– Endometrial antiproliferation

• Estrogen receptor (ER)

– Hypercoagulability

– Endometrial proliferation

• Androgen receptor (AR)

– Acne

– Hirsutism

– Hyperlipidemia

Biological Findings Associated

With Steroid Receptor Agonism• Mineralocorticoid receptor (MR)

–Salt and water retention

–Hypertension

–Weight gain

• Glucocorticoid receptor (GR)

–Decreased bone mineral density

– Immunosuppression

Norgestrel +++ +++ - ++++

Levonorgestrel ++++ +++ - ++++

Desogestrel ++ ++ - +

Gestodene +++ +/- - +

Norgestimate ++ +/- - ++

30

Background Information

Nomegestrol Acetate : Introduction1

Progesterone

NOMAC = nomegestrol acetate.

1. Schindler A. Maturitas. 2008;61:171–180.

NOMAC Activity similar to natural progesterone

Highly selective:

– Strong antigonadotropic activity

– No glucocorticoid, mineralocorticoid,

estrogenic or androgenic activity

46-hour half-life

VTE Risk with CHC

Rott H, Curr Opin Obstet Gynecol 2012, 24:235–240

VTE Risk with CHCRisk of VTE

Young healthy women 5 -10/10000

60-69 years old 1/1000

>80 years old 1/100

Pregnant 29/10000

Post partum 300-400/10000

BMI >30 OR 3

Progestogen

Cyproterone acetate OR 6.8

2nd Generation

levonorgestrel OR 3

3rd Generatiion

Gestodene OR 5.6

desogestrel OR 7.3

4th Generation

drospirenone OR 6.3

Rott H, Curr Opin Obstet Gynecol 2012, 24:235–240

Cochrane Review 2014: Combined oral contraceptives: venous thrombosis

• RECOMMENDED FIRST LINE COC : 30 µg of EE with levonorgestrel (LNG)

• EE (20 µg) has the lowest VTE risk but may also increase unscheduled bleeding that can adversely affect compliance.

• Other Progestogens (3rd and 4th generation) = 50%–80% VTE higher risk vs LNG

de Bastos et al. Combined oral contraceptives: venous thrombosis. Cochrane Database of Systematic Reviews 2014, Issue 3.

Progestogen

deficiency and

oestrogen excess

Progestogen excess

and oestrogen

deficiency

Excessive bleeding, clots Increased appetite

Breakthrough bleeding Acne, oily skin

Headaches during active

pills

Headaches during

placebo

Corneal oedema Oligomenorrhoea,

amenorrhoea

Breast tenderness &

Nausea

Irritability, depression,

mood changes

Leucorrhoea Vaginal dryness

Approach to some CHC side effects

Adolescent

• Typical-use failure rates for COCs: 15% to 26% vs 9%

• Promote LARC usage

• Dual protection

Young people’s concerns

• Weight gain

– no evidence with combined hormonal contraception (CHC) use.

– ↑ with DMPA

– little evidence for CAUSAL association with other progestogen contraception

FSRH CEU : contraceptive Choices for young people. 2010

Young people’s concerns

• Mood Changes and Depression

– hormonal contraception may be associated with mood changes

– no evidence that causes depression.

• Fertility

– no delay in return of fertility except for DMPA/ NET

Adolescent health concerns

• Bone Health

– progestogen-only injectable contraceptive associated with a small ↓BMD

– usually recovers after discontinuation.

– DMPA can be used < 18 years after consideration of other methods.

– Review DMPA use every 2 years to reassess the benefits and risks.

•

Adolescent non contraceptive benefits

• Bleeding Patterns and Dysmenorrhoea

– cycle control esp anovulatory cycles

– Heavy menstrual bleeding

– Primary dysmenorrhoea may improve with use of CHC.

Acne

• Any COC use can improve acne. – suppression of LH-driven androgen production by

ovaries

– induction of hepatic synthesis of SHBG → ↓Free androgen index

• If initial COC fails to improve acne →switch to a COC containing a less androgenic progestogen or one with a higher oestrogen content..

• progestogen-only implant may be associated with improvement, worsening or onset of acne.

Mid reproductive age

• Endometriosis = symptom control & disease progression– ANY progestogen – only method: LNG – IUS, ENG

implant, DPMA, oral dienogest (Visanne®), oral desogestrel (Cerazette®)

– CHC – especially tricycling or extended/ continuous regimens

– E2/NOMAC?

• PCOS = endometrial protection & hyperandrogenism– Any CHC– But especially anti-androgenic progestogen

Post Partum

• Closely spaced pregnancies < 1y postpartum → ↑ preterm birth, low birthweight and small-for-gestational-age babies.

• The risk of child mortality is highest for very short birth-to-pregnancy intervals (i.e. less than 12 months).

• Pregnancy can occur by 6 weeks if a woman does not exclusively breastfeed – important to make sure that a method is provided by

4 weeks postpartum.

www.rcog.org.uk/en/guidelines-research-services/guidelines/bpp1/

WHO MEC 2015

Perimenopause• unplanned pregnancies the same ratio as

young women

• Pregnancies are at high risk for maternal complications and poor outcomes such as miscarriage or chromosomal abnormalities

WHO MEC 2015

Non contraceptive benefits

• Irregular and Heavy menstrual bleeding– Any Combined Hormonal Contraception

– E2V/ Dienogest = FDA approved for heavy menstrual bleeding

– LNG-IUS = NICE guideline first line medical Mx• Endometrial protection with Hormone Therapy

– DMPA (beware hypo- oestrogenism and ↓BMD)

• Hot flushes and vaginal dryness– any oestrogen containing

Non contraceptive benefits

• Continuous or extended regimens of CHC – heavy menstrual bleeding– Improved cycle-related symptoms :

• Tiredness• Bloating• menstrual migraine

– Unscheduled bleeding• more common• improved with a short hormone-free interval as needed

– Cochrane Review 2014*• similar bleeding, discontinuation rates, and reported

satisfaction as traditional

*Edelman et al. Continuous or extended cycle vs. cyclic use of combined hormonal contraceptives for contraception. Cochrane Database of Systematic Reviews 2014, Issue 7

Advice for perimenopausal women on when to

stop contraception

Contraceptivemethod

Advice on stopping contraception

Age <50 years Age ≥50 years

Non-hormonal Stop contraception after 2 years of amenorrhoea

Stop contraception after 1 year of amenorrhoea

CHC Can be continued to age 50 years*

Stop CHC at age 50 years and switch to a non-hormonal method or progestogen-only pill, then follow appropriate advice

* If a woman wishes to stop hormonal contraception before age 50 years she should beadvised to switch to a non-hormonal method and to stop once she has been amenorrhoeicfor 2 years (or 3 years if switched from DMPA due to the potential delay in return ofovulation).

Source: Contraception for women aged over 40 years, Clinical Effectiveness Unit, 2010

Advice for perimenopausal women on when to stop contraception

Contraceptivemethod

Advice on stopping contraception

Age <50 years Age ≥50 years

DMPA Can be continued toage 50 years*

Stop DMPA at age 50 years and choose from options below:

switch to a non-hormonal method and stop after 2 yearsof amenorrhoea OR

switch to the POP, implant or LNG-IUS and follow advicebelow

Implant

POP

LNG-IUS

Can be continued toage 50 years orlonger*

Continue method

If amenorrhoeic either:

check FSH levels and stop method after 1 year if serumFSH is ≥30 IU/L on two occasions 6 weeks apart

or

stop at age 55 years when natural loss of fertility can beassumed for most women

If not amenorrhoeic, consider investigating any abnormalbleeding or changes in bleeding pattern, and continuecontraception beyond age 55 years until amenorrhoeic for 1year