Addi$onal Benefits of Oral Contracep$ves
Dr. Serdar Dilbaz Etlik Zübeyde Hanım Women’s Health Training and Research Hospital, Ankara, Turkey
1914-‐1921 Ac$vist Margaret Sanger coins the term “birth control,” opens first birth control clinic in Brownsville
1934 Endocrinologist Gregory Pincus creates a test tube rabbit — and is vilified as a Frankenstein
1951 Sanger and Pincus meet at a dinner party in New York; she persuades him to work on a birth control pill
1951 Carl Djerassi, a chemist in Mexico City, creates a pill by synthesizing hormones from Mexican yams. On a chemical level, the pill
has been invented, but Djerassi isn’t equipped to test, produce or distribute it
1952 Pincus tests progesterone in rats and finds it works He meets gynecologist John Rock, who has already begun tes$ng chemical contracep$on in women.
Frank Colton, chief chemist at the pharmaceu$cal company
Searle, also independently develops synthe$c progesterone
1953 Sanger is the ac$vist behind the pill and Pincus the scien$st,
Katherine McCormick — biologist, women’s rights ac$vist and heiress to a great fortune
— is the money. She writes Pincus a check for $40,000 to conduct research
1954 Rock and Pincus conduct the first human trials on 50 women in MassachuseWs. It works.
1956 Large scale clinical trials are conducted in Puerto Rico The pill is deemed 100 percent effec$ve, but some serious side effects are ignored
1957 The FDA approves the pill, but only for severe menstrual disorders, not as a contracep$ve
An unusually large number of women report severe menstrual disorders
1960 The pill is approved for contracep$ve use
History of COC
11.2 million women use oral contracep$ve pills Ø 58% of these use least in part for noncontracep$ve reasons
Ø Moreover, 14% of pill users (more than 1.5 million women), about half of whom have never had sex, use the pill exclusively for noncontracep$ve reasons
Ø Related to noncontracep$ve benefits of COC, drug industry was focused on new compounds
Contracep$on and Beyond: The Health Benefits of Services Provided at Family
Planning Centers. GuWmacher Ins$tute 2013
Mechanisms of Oral Contracep$ves
Progestogen;
Ø endometrial atrophy
Ø cervical mucus thickening
Ø decreased tubal mo$lity
Ø provide the dominant contracep$ve benefit
Interrupts the hypothalamic-‐pituitary gonadal
axis by suppressing secre$on of luteinizing hormone
(progestogen) and follicle s$mula$ng hormone (estrogen)
to primarily prevent ovula$on Crosignani PG, et al.Contracep$on 1996
Estrogen;
Ø stabilizes the endometrium to minimize breakthrough bleeding
Ø poten$ates the ac$on of progestogens Schindler AE, Campagnoli C, Druckmann R, et al. Maturitas 2008
Ø inhibi$ng the release of follicle-‐s$mula$ng hormone from the
pituitary Shulman LP, et al. Cancer Treat Res 2010
Estrogens
Dienogest
History of Proges$ns
Health Benefits of COCs
Gynecological Reproduc$ve Oncologic Other
Menstruel Bleeding
Disorders
Endometriosis /
Adenomyosis
Benign Breast Disease Rheumatoid Arthri$s
Dysmenorrhea Androgenisa$on Ovarian Cancer Voice
PMS Endometrial
Hyperplasia / Cancer
Mul$ple Sclerosis
Ovarian Cysts Colorectal Cancer Bone Structure
Leiomyoma Asthma
PID Menstrual Migraine
Ectopic pregnancy Social
Menstruel Bleeding Disorders
Significant blood loss decrease à %40 – 50 (Fraser IS. Aust N Z J Obstet Gynaecol. 1991)
Ø Cyclic Fashion à Decreaement of the hormone free interval à BeWer result (Sulak PJ.Obstet Gynecol.2000)
Ø Extended Cycle à Significant Endometrial safety (Anderson. Am J Obstet Gynecol.2006)
Ø Currently marketed OCs à Not approved by FDA except «Dienogest / Estradiol Valerate» (2012)
especially newer and lower-‐dosed COCs, all reduce the volume of
blood loss with conven$onal use Luis Bahamondes et al. Human Reproduc$on Update, 2015
Dysmenorrhea
Ø Proges$n dominant effect à Endometrial atrophy à Rela$vely lower cytokines
Ø Combined OC vs Placebo à Pain improvement OR 2.01 (Wong CL. Cochrane Data Sys Rev. 2011)
Ø COCs à Uterine prostoglandins
Symptoma$c relief upto %70-‐80 (Hendrix SL. Contracep$on 2002)
Ø Low or medium dose estradiol is effec$ve
Ø Third genera$on proges$ns à More effec$ve than the previous ones
Oral contracep$ves for pain relief from dysmenorrhea: a review
Hans-‐Peter Zahradnik, 2010
ACOG Noncontracep$ve Uses of Hormonal Contracep$ves (Jan 2010)
Ø Limited data suggest that COCs can reduce the severity of dysmenorrhea in women with endometriosis
Ø Con$nuous COCs may offer addi$onal benefit by elimina$on of menstrua$on and associated dysmenorrhea
PMS Ø Maybe first line therapy
(Lopez LM. Cochrane Database Syst Rev. 2009)
Ø Drospirenone à Strongest evidence for PMS / PMDD
(strong an$-‐mineralocor$coid effect)
Yonkers KA. Obstet Gynecol. 2005 , Lopez LM. Cochrane Database Syst Rev. 2012
Sillem M. Et al. Womens Health (Lond Engl). 2006
Ø 4 days of interval beWer than 7 days
Ovarian Cysts Cyclic suppression à FSH suppression à Reduce follicular and luteal cysts
No clinical significance
Ø Combined OCs à Do not hasten the resolu$on of exis$ng cysts (Bayar U. Int J Gynaecol Obstet. 2005)
Ø Cys$c masses that did not resolve within several months were probably
NOT func$onal cysts Grimes D et al.Cochrane Database of Systema$c Reviews 2014
Leiomyomas Endometrial atrophy
Ø Risk of myoma reduced among post-‐treatment and constant users of COC
Ø The risk decreases with longer use
Ross Rk et al. Br Med J (Clin Res Ed). 1986
Ø 70% reduc$on of myoma size, who used the pills for seven and more years, demonstrated a 50% reduc$on of myoma size
Chiaffarino F, et al. Br J Obstet Gynaecol. 1999
BUT THEY ARE OLD STUDIES AND THERE IS NOT ANY HIGH LEVEL NEW EVIDENCE
Pelvic Inflammatory Disease (PID) Ø Proges$n à Cervical mucus thickening à Inhıbi$ng the ascending pathway
Ø Diminished menstrua$on à Decresased retrograde menstrua$on
Ø Reduc$on in hospitaliza$on days, amount of medica$on and opera$ve procedures and also the risk of ectopic pregnancy and infer$lity problems
(Kaunitz AM. Contracep$on. 1999)
Ø Do not have a role in reduc$on of upper genital tract infec$on
(Ness R. AJOG. 2001)
Ø Reduce the risk of PID by 50% to 60%
(Burkman RT. Et al. Clin Obstet Gynecol. 2001)
Ectopic pregnancy
Ø The primary mechanism providing effec$ve pregnancy
preven$on
Ø COCs use reduce the risk of PID and related to this reduces the
risk of ectopic pregnancy Burkman R, et al. Am J Obstet Gynecol 2004
Ø There is evidence that women who become pregnant while on
proges$n-‐only oral contracep$ves may have a higher
likelihood of that pregnancy being extrauterine Furlong LA. Et al. J Reprod Med 2002
Androgenisa$on
Ø Decreasing serum-‐free testosterone concentra$ons
Ø Inhibi$ng luteinising hormone s$mula$on of ovarian androgens
Ø Increasing SHBG
Ø Inhibiting 5-‐alpha reductase Thorneycroo IH, et al. Contracep$on 1999
Arowojolu AO, et al. Cochrane Database Syst Rev 2009;(7):CD004425.29
Acne: OCs vs placebo for 6 cycles OR: 3.41 (Koltun W. Eur J Obstet Gynecol Reprod Bio. 2011)
Total lesion count reduc$on: %55 vs %39 (Palombo-‐Kinne E. Contracep$on. 2009)
Androgenic Effects of Proges$ns
An$-‐androjenic effect
Androgenisa$on (hirsu$sm–acne)
Ø The highest an$-‐androgenic progestogen is cyproterone acetate Schindler AE. Eur J Obstet Gynecol Reprod Biol. 2004
Ø Normaliza$on of the ovaries in structure and size in women with
PCOS
Ø COCs are likely to be effec$ve in the treatment of acne
Ø COCs reduced acne severity and lesion counts Carey and Allen. 2012 Royal College of Obstetricians and Gynaecologists
• The effect lasted aoer the pill cessa$on
• Drospirenone and dienogest containing COCs are effec$ve in hirsu$sm Breitkopf DM, et al. Contracep$on 2003; Batukan C, et al . Fer$l Steril 2006;
Ø COCs with lower androgenic proges$ns should be used
Endometriosis Progestogenic effect and ovulatory inhibiton à Endometrial atrophy in ectopic $ssue
Ø Risk of endometriosis is reduced in pill users Vercellini P, et al. Hum Reprod Update. 2011
Ø COC reduce the severity of dysmenorrhea in women with endometriosis. Significant reduc$on in pain Harada T. Fer;l Steril. 2008, Schindler AE. Et al. Minerva Ginecol. 2004
Ø Symptoms presumed due to endometriosis with combined hormonal contracep$ves ESHRE guideline: management of women with endometriosis Human Reproduc;on, 2014
Ø Significant postopera$ve preven$on Serrachioli R. Hum Repord.2009
Ø Con$niuous OC vs GnRH agonist: Similar effect Guzick DS. Fer;l Steril. 2011
Ø Con$nuous use of a combined oral contracep$ve pill is more effec$ve Vercellini P, et al.Fer$l Steril 2003
Ø Arer cystectomy for endometrioma, hormonal contracep$ves (COCs…) → secondary preven$on Vercellini et al., Reprod Biomed Online 2010
Adenomyosis
Ø Adenomyosis related symptoms is reduced by oral hormonal
contracep$ves Maia H, et al. Gynecol Endocrinol. 2006.
Ø Best choice for adenomyosis-‐related pain is con$nuous use
Monophasic, low-‐dose COC • safety
• good efficacy
• appreciable tolerability
• low cost, Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis:
pathogenesis and treatment. Nat Rev Endocrinol 2013;
Progestogenic effect of progestagens
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Oettel M et al. Gynecol Endocrinol 2001
Benign Breast Disease Ø Older studies with 50 mcg estradiol à Protec$ve effect
L.A. Brinton. Am J. Epid 1981
Ø < 50 mcg estradiol à Similar effec$vite
Ø All types of COCs reduce the incidence of benign breast disease § Fibrocys$c breast disease
§ Fibroadenoma
§ Undefined breast lumps
Ø Controversy COC use in BRCA1/2 muta$on carriers increases their risk of developing breast cancer
Ø COCs use consistently →increased risk is small →but sta$s$cally significant
Ovarian cancer -‐ I
• Possible mechanisms; • reduc$on/elimina$on of ovula$on
• significant increase in apoptosis of the ovarian epithelium with proges$ns, either alone or in combina$on with an estrogen
in animal studies
• a high potency proges$n may be more effec$ve ?? Rodriguez GC,et al. J Soc Gynecol Inves$g 1998, Rodriguez GC, et al. Cancer Prev Res (Phila) 2013, Schildkraut JM, et al. J NatlCancer Inst 2002
• high-‐grade serous EOCs arise the distal fallopian tube COCs may be relevant to a similar effect on the fallopian tube
• low-‐dose COCs (<35 micrograms estrogen) as protec$ve effect as high ones
Ovarian cancer -‐ II
• a significant reduc$on in ovarian cancer in ever-‐users
compared with never-‐users
• dura$on–response rela$onship, with a reduc$on in incidence
of 50% among women using COCs for 10 or more years Havrilesky LJ, et al.Obstet Gynecol 2013
• risk decreases by 20% for each 5 years of use the protec$ve
effect presents 30 years arer stopping. Beral V, et al. Lancet 2008
Ovarian cancer -‐ III
Risk Reduc$on by Years of Use Rela$ve Risk
(log scale)
0.1
1.0
10.0
1 12 6 2 11 10 9 8 7 3 5 4
CASH, 1987
Beral et al, 1988
La Vecchia et al, 1986
Wu et al, 1988
years
Adapted from Grimes DA et al, eds. Modern Contracep$on: Updates from The Contracep$on Report. Emron, 1997.
≥10 <.5 <1 1–4 5-‐9 5 ≥5
COCs Protect Against Ovarian Cancer aoer Discon$nua$on
Rela$ve Risk
0.1
1.0
10.0 CASH, 1987
WHO, 1989
La Vecchia et al, 1986
Rosenberg et al,1982
years after discontinuation
Stanford JL. Contracep;on. 1991;43:543-‐556.
<
Use of COCs on high risk women
BRCA1 and BRCA2 muta$ons increase the risk of ovarian cancer Ø BRCA 1 45% risk
Ø BRCA 2 25% risk
COCs reduce the ovarian cancer risk for women BRCA1 and BRCA2 muta$on ◦ COCs use ≤3 years 20%
◦ COCs use ≥6 years 60%
Narod SA et al. N Engl J Med. 1998, Shulman LP, Dungan JS. Et al. Cancer Treat Res 2010, Gadducci A, et al. Ann Oncol 2013
www.contracep$ononline.org
Endometrial cancer -‐ I
• The mechanism:
Ø overall suppressive effect of COCs on endometrial prolifera$on
Endometrial cancer -‐ II
• compared with never-‐users of COC, ever-‐users a significant
reduc$on in the risk of endometrial cancer Hannaford PC, et al. BMJ 2010
• 50% reduc$on in the risk of endometrial cancer→used at least
for one year.
• the risk-‐reducing effect persists arer discon$nua$on Luis Bahamondes et al. Human Reproduc$on Update, 2015
• protec$ve effect increases with the dura$on of use and
persists more than 20 or more years arer discon$nua$on
COCs and Endometrial Cancer
Risk reduc$on of endometrial cancer
4 years of use %56
8 years of use %67 12 years of use %72
Schlesselman, 1998
Type of end.Ca ◦ Adeno Ca ◦ Adenoskuamöz Ca ◦ Adenoakantoma
Endometrial Hyperplasia & Cancer
(Collabora$ve Group on Epidemiological Studies on Endometrial Cancer. Lancet Onco. 2016)
Endometrial Hyperplasia & Cancer
Ø Medium to long term use
Significant preven$on
Ø Similar preven$on rate as ovarian cancer
Ø Effect resumes arer 30 years from cessa$on
Adapted from Schlesselman JJ. Hum Reprod. 1997
years aoer discon$nua$on
Rela$f Risk
10
0 2 4 6 8 10 12 14 16 18 24 20 22
0.1
1
0.01
Years RR 5 0.33
10 0.41 20 0.51
COCs Protect Against Endometrial Cancer Aoer Discon$nua$on
La Vecchia, 1986
CASH, 1987
Levi et al, 1991
Stanford et al, 1993
Hulka et al, 1982
Kaufman et al, 1980
Weiss et al, 1980
Colorectal Cancer -‐I
• COCs for 96 months or longer had a 40% lower risk of developing colorectal cancer
Mar$nez ME, et al. Cancer Epidemiol Biomarkers Prev 1997
• 18% reduc$on in colorectal cancer among COC users compared with never-‐users
• RR for ever COCs use Ø Colon Cancer: 0.80
Ø Rectal Cancer: 0.85
Boser C. Hum Reprod Update. 2009
Colorectal Cancer -‐II
• S$ll unclear whether the dose of COCs plays a role in colorectal
cancer preven$on. Carey and Allen. 2012 Royal College of Obstetricians and Gynaecologists
• High benefits of COCs especially among reproduc$ve-‐aged
women with Lynch syndrome Lu KH, Daniels M. Cancer 2013
• No risk reduc$on was found for distal large bowel cancer
through use of COCs Long MD, et al. Am J Gastroenterol. 2010
Other Non-‐Gynecologic Benefits Ø BMD: Conflic$ng data
§ Especially in hypoestrogenic women Williams JK. Int J Fer$l Womens Med. 2000
Ø Asthma: Reduced risk of physician diagnosed asthma OR: 0,68 § > 3 asthma aWacks: OR: 0,45 Nwaru BI. J R Soc Med. 2015
Ø Rheumatoid Arthri$s: Conflic$ng data § Symptoma$c relief at inflammatory arthri$s
§ Risk of RA RR=0.88, 95% CI=0.75-‐1.03 Albreth K.Arthri$s Care Res. 2016, Qi S.Ther Clin Risk Manag. 2014
Ø Mul$ple Sclerosis: Use of OC may increase incidence OR: 1.52
Hellwig K.PLoS One.2016 § OC + Inf β à Decreasing ac$ve brain lesions and may be used as a treatment
Pozzilli C. Neurol Neuroimmun. 2015
Ø Voice : Androgen excess in climacterium can lead to voice improvement
La FM et al. J Voice 2007
Ø Menstrual Migraine: without aura is just minimal changes in hormonal concentra$ons
Kuhl H et al, Ther Umsch. 2009; Sulak P et al, Headache. 2007
Birth Control Advances Women’s Economic Empowerment
Birth Control Advances Women’s Educa$onal Opportuni$es
Access to Contracep$on Has Also Led to More College-‐Educated Women Pursuing Advanced Professional Degrees
Birth Control Enhances Children’s Well-‐Being in the Long Run
Birth Control Reduces Teen Pregnancy
Birth Control Reduces Unintended Pregnancy
Social and Health Benefits Birth Control Has Expanded Opportunity for Women
Mother age vs.infant mortality
Unintended pregnancy & saving money
Thank you for your attention