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Hormonal contraception

Combined hormonal contraceptives
Hans-Joachim Ahrendt, Magdeburg Praxis für Frauenheilkunde, Klinische Forschung und Weiterbildung (Clinical research and further education), Magdeburg, Germany Reviewers: Kai J. Bühling, Hamburg e Medicine
and Petra Stute, Bern Summary
In the past years, hormonal contraception underwent sub-
stantial development. The dose of ethinylestradiol (EE) has
continuously been decreased to reduce the risk of venous
thromboembolism. Estradiol valerate (E2V), a "natural"
estrogen, is now contained in a novel combined oral contra-ceptive (E2V/DNG). Recently developed progestins havebeen introduced to market for instance as progestin-only preparations. New progestins exert antimineralocorticoidand antiandrogenic activity (beneficial for mastodynia oredemas and skin and hair issues, respectively). The tradi-tional schedule of administration of oral hormonal contra-ceptives is being challenged and for several preparations,the hormone-free interval has been reduced to four or twodays. Extended-cycle birth control has become commonpractice. It provides an opportunity for the alleviation of side effects associated with menstruation (PMS/PMDD, i. e.
menstrual migraine). In this context, also the non-oral hor-monal contraceptive methods, the vaginal ring and thehormone patch, are discussed.
Introduction
Birth control consultation is part of a gynecologist's daily
Downloaded from cme.akademos.de on Friday, October 7, 2016 routine and thus easily underestimated. Upon closer in- Copyright 2016 akademos Wissenschaftsverlag. All rights reserved spection, considerable progress has been made in the pastfew years, whereby hormonal contraceptive methods havesurpassed the initially simple intention of birth control.
In addition, patients have become more demanding, asthey usually possess thorough knowledge and experiencewith contraceptives and seek the gynecologist's advicewith specific expectations.
Ahrendt H.-J. Hormonal . Gynakol Geburtsmed Gynakol Endokrinol 2009; 5(2): 68–81 published 31.07.09 www.akademos.de/gyn akademos Wissenschaftsverlag 2009 ISSN 1614-8533 Nowadays, the prescription of a contraceptive encompas- ses more than merely birth control due to considerableprogress in the non-contraceptive properties. Recent in- vestigations and clinical experience provide insight intothe potential of hormonal contraceptives to reduce gyne- cological symptoms (e. g. dysmenorrhea, hypermenorrhea,mastodynia, premenstrual syndrome), avoid side effects commonly associated with menstruation (menstrual migraine, abdominal pain) or treat androgen-related health conditions (e. g. blemished skin, seborrhea, acne).
Due to recent scientific data and a wider range of prepara-tions, contraceptives can nowadays be prescribed to pa- tients with severe health risks such as hereditary thrombo- philia or to those who have suffered from thrombosis, heart attack or hypertension.
This continuous progress in hormone-based as well as non-hormonal birth control methods demands specialized knowledge in order to individually consult our patients in selecting the adequate contraceptive.
The following developments were seminal during the last Figure 1: Application of contraceptives in percent (BZgA 2007; n = 1501) • Continuous reduction of ethinylestradiol doses • Introduction of estradiol valerate • Reduction of synthetic progestin doses In 1959, the first oral hormonal contraceptive, Enovid® was • Development of new synthetic progestins approved in the USA. It contained 75 μg ethinylestradiol and 5 mg norethynodrel. The first oral contraceptive intro- 3. Shortened hormone-free interval duced in Germany was Anovlar® in 1961 (50 μg ethinylest- • From a seven-day to a four-day or two-day hormone- radiol and 4 mg norethisterone acetate).
• Continuous-cycle regimen (Off-label-use) Mode of action and contraceptive safety
Downloaded from cme.akademos.de on Friday, October 7, 2016 4. New routes of administration of hormonal contracepti- The two primary mechanisms of action (Table 1) of com- Copyright 2016 akademos Wissenschaftsverlag. All rights reserved bined hormonal contraceptives are the central inhibition of • intrauterine, vaginal, transdermal, subdermal the hypothalamic-pituitary-ovary axis (inhibition of ovula- 5. Broadened spectrum of non-hormonal contraceptive tion) and the functional inhibition of the three peripheral components cervix, endometrium and fallopian tube exer-ted by the synthetic progestins.
In Germany, 86% of women between 20 and 29 years and68% between 30 and 44 years actively and consciouslymake use of birth control. Hormonal contraceptives are still Table 1: Mode of action of contraceptives the most commonly used method (Fig.1) (BZgA 2007).
Inhibition of GnRH Anterior pituitary Inhibition of LH and FSH Inhibition of follicle maturation Disturbance of ovum transport Inhibition of nidation Cervical mucus thickening The contraceptive safety is calculated with the inter- In contrast to estradiol valerate, degradation is inhibited by nationally comparable Pearl Index (PI):The number of the 17α-ethinyl residue. Furthermore, this residue prevents unintended pregnancies in 100 woman-years of exposure conversion to estrone (E1). EE does not bind to the sex hor- divided by the number of menstrual cycles. A "safe" mone-binding globulin (SHBG) and has a more pronounced contraceptive method has a PI of 1. If a healthy and fertile effect on the endometrium than estradiol. However, EE and couple does not make use of contraceptives, the PI lies at estradiol (E2) increase the concentration of SHBG, which approximately 80, meaning that 80% of the women turn binds free testosterone making it biologically inactive pregnant within one year.
(Timmer and Geurts 1999).
Number of unintended pregnancies x 100x 12 In 2009, the first preparation containing estradiol valerate (E2V, Fig. 3) was introduced to the market.
Number of menstrual cycles Furthermore, the "perfect use PI" excludes any pregnanciescaused by the incorrect use of the method. Thus, a methodbearing a high risk for incorrect use is characterized by agreat discrepancy in the PI and the perfect PI. Both PIs are relevant for assessing the method: If a patient is interestedin the safety of a method provided it is correctly used (i. e.
the pill when regularly taken), the perfect PI applies.
Composition of hormonal contraceptives
The "classical" pill is a combined oral contraceptive con-sisting of an estrogen and a progestin. However, alternati- ves are oral and non-oral estrogen-free preparations, alsoknown as progestin-only preparations.
Figure 3: Structure of estradiol valerate Until now, 17α-ethinylestradiol (EE) was the most frequentestrogen contained in oral contraceptives (Table 2, Fig. 2). Inthe past decades, the dose was continuously reduced from Estradiol valerate is quickly absorbed, hydrolyzed and, an initial 75 μg to 50 μg, 35 μg and 30 μg, down to eventu- within a few minutes, converted to estradiol, whereby ally 20 μg and 15 μg in order to minimize unintended side exerting the same estrogenic effects. 1 mg E2V is equiva- effects, especially the risk for thromboembolism.
lent to 0.76 mg E2.
Downloaded from cme.akademos.de on Friday, October 7, 2016 However, depending on the target organ, E2V differs in its Copyright 2016 akademos Wissenschaftsverlag. All rights reserved effectiveness on the receptor. Thus, 2 mg E2V can have thesame biological effect than 4 to 20 μg ethinylestradiol.
Regarding its inhibitory effect on the follicle-stimulating hormone (FSH) and the stimulation of the endometrium, the dose corresponds to 20 μg EE, while it is equivalent to more than 20 μg EE concerning its effect on cell maturation of vaginal epithelial cells and less than 20 μg EE concerningprotein synthesis in the liver (SHBG, angiotensinogen andhemostasis parameters (Data on file (B709); Endrikat et al.
2008; Helgason 1982; Lindberg et al. 1989; Mashchak et al.
1982; Wiegratz et al. 2004).
Figure 2: Structure of ethinylestradiol Ahrendt H.-J. Hormonal . Gynakol Geburtsmed Gynakol Endokrinol 2009; 5(2): 68–81 published 31.07.09 www.akademos.de/gyn akademos Wissenschaftsverlag 2009 ISSN 1614-8533 Progestins
Progestins included in hormonal contraceptive pills not
only ensure contraceptive safety but also have additional
properties (see Table 4).
The different progestin groups are shown in Figure 4.
* Drospirenone is a with progesterone * Dienogest is a derivative of 19-nortestosterone with progestogene • Drospirenone* Figure 4: Classification of progestins CMA: Chlormadinone acetate; CPA: Cyproterone acetate; LNG: Levon- orgestrel; NET: Norethisterone; NETA: Norethisterone acetate The synthetic progestins suppress preovulatory LH increase Table 2: Ovulation inhibition dose (per day) and half-time of different and thus impair ovulation. The preparations usually con- oral progestins (Kuhl and Jung-Hoffmann 1999) tain a 1,5- to 2-fold ovulation inhibition dose (Table 2). Addi- Downloaded from cme.akademos.de on Friday, October 7, 2016 tionally, they exert contraceptive activity by their periphe- Copyright 2016 akademos Wissenschaftsverlag. All rights reserved ral effect on the cervix, the endometrium and the fallopian Chlormadinone acetate Cyproterone acetate Norethisterone acetate To a great extent, the partial activities of the synthetic • Mini-pills: Progestin without ovulation inhibition progestins (Tab. 3) determine the non-contraceptive bene- • Progestin-only pill: Progestin with complete ovulation fits of a preparation inhibition and a 12-hour window of effectiveness • Post-coital contraception: high-dose progestin Tabelle 3: Partial action profile of progestins (Kuhl and Jung-Hoffmann 1999) Preparations with antiandrogenic activity
Patients presenting with signs for hyperandrogenemia
(blemished skin, seborrhoea, acne and hirsutism) should
receive a combined oral contraceptive pill that contains aprogestin with antiandrogenic activity (Table 4). In more Chlormadinone acetate severe cases, continuous-cycle use without a hormone-free Cyproterone acetate interval is recommended.
Table 4: Hormonal contraceptives with antiandrogenic activity Cyproterone acetate* Diane 35® Juliette®, BellaHexal®, Attempta ratio35®, Cyproderm®, Morea®, Ergalea®, Clevia®, Jennifer® Norethisterone acetate Valette®**, Qlaira® Petibelle®, Yasmin®, Yasminelle®, Aida®, YAZ® G = progesterone activity; E = estrogenic activity; Anti-E = anti-estro- genic activity; A = androgenic activity; Anti-A = antiandrogenic activity; Belara®, Balanca® Gluc = glucocorticoid activity; Anti-Min = antimineralocorticoid * All preparations containing cyproterone are not officially approved When selecting a preparation, the additional properties of for hormonal contraceptive use despite their contraceptive activity the progestins play a pivotal role, especially the androgenic by ovulation inhibition. Approved indications are: therapy of andro- (libido impairment), the antiandrogenic (blemished skin or genization symptoms in women (acne, mild hirsutism, androgenic acne) as well as the antimineralocorticoid activities (ten- Downloaded from cme.akademos.de on Friday, October 7, 2016 dency for water retention).
** Valette®, containing the progestin dienogest (DNG), is approved as Copyright 2016 akademos Wissenschaftsverlag. All rights reserved a hormonal contraceptive as well as for the treatment of mild and moderately severe androgenization: blemished skin, mild to Combined oral contraceptives containing estrogen and
moderately severe acne progestin
Oral contraception (OC) is the most frequently used me-
thod of hormonal contraception. The following formula-
Preparations with antimineralocorticoid activity
tions are available: Apart from their antiandrogenic activity, all preparations • Combined methods containing an estrogen and a containing drospirenone (see Table 4) also exert antimine- ralocorticoid activity. Thus, they are not only suitable for • Monophasic preparations: same amount of estrogen patients with skin and hair problems, but also for patients and progestin in each active pill in a pack that tend to suffer from water-retention-related weight • Biphasic preparations: altering hormone levels once gain and mastodynia. Various studies could show that during the menstrual cycle weight gain is not as pronounced in preparations contain- • Triphasic preparations: three different doses of ing drospirenone compared to other progestins and, if estrogens and progestins in one pack present, rather reflects the physiological age-dependent • Multiphasic preparations: Estrogens and progestins in weight gain.
• Sequential preparations Extended– and continuous-cycle oral contraceptives
• First phase: estrogens Extended-cycle use is defined as the consecutive admini- • Second phase: estrogens and progestins stration of combined oral contraceptive pills for several • Progestin-only pills cycles (3, 4, 6 or 9 cycles), followed by a 7-day hormone-free Ahrendt H.-J. Hormonal . Gynakol Geburtsmed Gynakol Endokrinol 2009; 5(2): 68–81 published 31.07.09 www.akademos.de/gyn akademos Wissenschaftsverlag 2009 ISSN 1614-8533 interval. In continuous-cycle use, the preparation is taken considered as off-label-use.
for more than a year without a break (see Fig. 5). However, Indications for continuous-cycle use are (referring to in the near future, only those preparations with a flexible Göretzlehner, 2009): extended-cycle scheme will prove successful. Here, the patient decides if and when to include the hormone-free • Bleeding disorders interval. In general, withdrawal bleeding should be induced • Hypermenorrhea if the patient experiences the side effects of the extended- cycle use, such as severe mastodynia, long-lasting break- through bleedings or spotting. The ideal length of the • Irregular bleedings hormone-free interval is four days (Göretzlehner et al. 2009).
• Dysmenorrhea• Premenstrual syndrome (PMS) Extended-cycle use Menstrual cycle-dependent gynecologic diseases• Uterine fibroids• Endometriosis • Polycystic ovaries (PCO)• Functional cysts• Androgenization (Acne, seborrhea, hirsutism) Continuous-cycle use Menstrual cycle-dependent systemic symptoms 7-day pill-free interval, • Menstrual migraine withdrawal bleeding • Iron deficiency – anaemia• Depressions• Genital herpes Figure 5: Diagram to illustrate the duration of administration • Diabetes mellitus• Multiple sclerosis The extended-cycle administration regimens have been Downloaded from cme.akademos.de on Friday, October 7, 2016 developed by practicing gynecologists on the basis of their Copyright 2016 akademos Wissenschaftsverlag. All rights reserved clinical experience. An extended-cycle scheme eliminateswithdrawal bleeding thus providing a means to reduce Delay or suppression of menstruation menstrual-related symptoms such as dysmenorrhea and irregular bleedings as well as alleviate endometriosis- related symptoms or menstrual migraine.
• Holidays• Hygienic factors A study carried out in Germany in 2007 (BZgA 2007) dis-covered that 57% of the women prefer an extended-cycle Extensive practical experience has been gained with the administration scheme. 26% of the participants wish to extended-cycle use of Valette® (0,03 mg EE and 2,0 mg have fewer periods and an additional 31% would appreciate dienogest). The acquired data suggest that contraceptive a possibility to postpone menstruation on special occas- safety is acceptable due to the continuous administration ions, for instance when on holiday. Meanwhile, data from regimen. Missed tablets do not impair contraceptive acti- two randomized studies of preparations approved in Ger- vity, as this period is too short for the onset of endogenous many (30 μg EE/2 mg DNG, Valette®, EE/DSG, NuvaRing®) estradiol production or follicle maturation. Contraceptive have been published (Miller et al. 2005) that exclusively protection is considered to last for at least seven days, investigate bleeding response in extended-cycle regimens.
equivalent to the omission of seven active tablets during However, so far no preparation has officially been approved the pill-free week.
for extended-cycle use by the BfArM.
If present, irregular bleeding occurs more frequently during Several observational studies with various preparations the first two blister packs and thereafter only in 8% of the (30 μg EE/2 mg DNG, EE/CMA, EE/DRSP) have also proven women. Irregular bleeding patterns can be found more positive effects on cycle-dependent complaints. Neverthe- often in smokers and in patients that had previously ex- less, the following listed indications have still got to be perienced irregular bleedings.
Apart from the irregular bleedings, mastodynia is a habi- estrogen and progestin doses. Furthermore, shortening the tual side effect. In general, compliance is good in a contin- interval alleviates menstrual cycle-dependent complaints uous-cycle administration regimen. Which of the available such as dysmenorrhea, premenstrual syndrome (PMS), combination preparations are suitable for extended-cycle premenstrual dysphoric disorder (PMDD) as well as men- use/continuous-cycle use has only been confirmed for strual migraine that persist in a 21+7-day administration three preparations that have already been part of clinical trials (Valette®, Yasmin® und Nuva-Ring®). However, sever-al other preparations have proven successful for this pur- The oral contraceptive YAZ® containing 20 mg EE and 3 mg pose in clinical practice.
drospirenone, similar to Yasminelle® and Aida®, only in-cludes a 4-day interval (Fig. 6). Consequently, hormonal Abridgement of hormone-free interval: four-day hormone-
fluctuation and withdrawal symptoms are reduced. Clear- free interval in combined oral contraceptive pills (EE 20 μg
ance of drospirenone extends into the hormone-free inter- and DRSP 3 mg)
val, as its half-life is 31 hours. This additionally reduces For the last 50 years, the rigid administration scheme of 21 menstrual cycle-dependent symptoms and enhances the days of active tablets followed by a seven-day hormone- antiandrogenic and antimineralocorticoid activity.
free interval (Fig. 6) has proven successful. This seven-dayinterval was necessary in order to eliminate the initially In general, the dose regimen 24+4 has the benefits of high doses of estrogens and progestins (originally 75 μg EE continuous-cycle use, but withdrawal bleedings remain.
and 5 mg norethynodrel). However, a long interval bears a This is of importance for those women who prefer the potential risk for contraception, as there is a possibility for reassurance of monthly withdrawal bleedings (42%) but the onset of endogenous estradiol production and follicle want to benefit from the advantages of the continuous- maturation. A shorter pill-free interval is thus beneficial and nowadays feasible due to the substantial reduction in Conventional hormone-free interval
seven-day interval seven-day interval Downloaded from cme.akademos.de on Friday, October 7, 2016 Copyright 2016 akademos Wissenschaftsverlag. All rights reserved Shortened hormone-free interval
four-day interval four-day interval Drospirenone 3 mg Drospirenone 3 mg Drospirenone 3 mg Figure 6: Administration schemes of oral contraceptives Ahrendt H.-J. Hormonal . Gynakol Geburtsmed Gynakol Endokrinol 2009; 5(2): 68–81 published 31.07.09 www.akademos.de/gyn akademos Wissenschaftsverlag 2009 ISSN 1614-8533 • YAZ® is the only oral contraceptive with clinically proven Bleeding regularity and the intensity of the withdrawal effect on emotional and physical symptoms in PMDD, the bleeding was analogous to the equivalent preparation most severe form of PMS (Pearlstein et al. 2005).
levonorgestrel (LNG), which includes a seven-day hormone-free interval. Likewise, there was no significant difference "Natural" estrogen: oral combined contraceptives con-
in irregular bleedings (Bachmann and Sulak 2004; Gruber taining estradiol valerate
et al. 2006).
For the first time, a combined oral contraceptive containingestradiol valerate (E2V) and dienogest (Qlaira®) was intro- Additionally, the non-contraceptive properties have proven duced to the market, a preparation that is characterized by its cycle stability. E2V is quickly absorbed, hydrolyzed and • Acne: In two placebo-controlled studies a total of 1072 then converted to estradiol (E2), the active substance.
women aged 14 to 45 years with a moderately severe However, the only available preparation so far was Femilar® facial acne were treated with six cycles of YAZ®. Mean (E2V, CPA; Finland), which has proven unacceptable in reduction of inflammatory lesion count was 55% com terms of bleeding patterns (Astedt et al. 1977; Astedt et al.
pared to 32% in the placebo group (Koltun et al. 2006; 1979; Kivinen and Saure 1996; Serup et al. 1979; World Lucky et al. 2006).
Health Organization 1980). E2-based oral combination • PMS/PMDD: Premenstrual disorders are prevalent in up to preparations lead to an increase in bleeding disorders, as 80% of women (Hylan et al. 1999; Ramcharan et al. 1992; the 17μ-hydroxy steroid dehydrogenase type 2 (stimulated Wittchen et al. 2002; Woods et al. 1932) between 30 years by progestins) quickly converts E2 into E1 (estrone). E1, how- and onset of menopause. Thus, 25% of all women suffer ever, does not show any proliferative effect on the endome- from severe distress associated with PMS (Angst et al.
2001; Wittchen et al. 2002). In approximately 5% of cases,symptoms are severe, also known as PMDD (American By applying a dynamic dose regimen, the rate of unschedu- Psychiatric Association 1994; Angst et al. 2001; Andersch led bleeding has been adapted to that of the EE pills. The et al. 1986; Cohen et al. 2002; Johnson et al. 1988; dose regimen illustrated in Figure 7 has proven successful.
Ramcharan et al. 1992; Rivera-Tovar and Frank 1990;Sveindottir and Bäckström 2000; Wittchen et al. 2002; Figure 8 shows that serum-estradiol levels are constant Woods et al. 1982).
• In a crossover comparison of YAZ® versus placebo, the symptom scores of patients with PMDD were reduced by almost 50%.
Day 1 and 2:
Day 3 to 7:
Day 25 to 26:
3 mg E2V at the beginning Balanced estrogen- 1 mg E2V at the end for less Downloaded from cme.akademos.de on Friday, October 7, 2016 for a quick hemostasis and progestin doses for contra- hormone fluctuations Copyright 2016 akademos Wissenschaftsverlag. All rights reserved a short withdrawal bleeding ceptive safety and high-level during the complete administration cycle Estradiol valerate step-down
Hormone-free tablets Day 3 to 24:
Day 8 to 24:
After Day 24:
Day 27 and 28:
Dienogest with at least a Predominance of progestin Sudden decrease in Two hormone-free tablets 2-fold ovulation inhibition (3 mg dienogest) for high dienogest serum levels for for increased convenience dose over 22 days for high- cycle stability until the end the punctual onset of level contraceptive safety withdrawal bleeding Figure 7: Dynamic dose regimen (Lu et al. 2007) Estradiol (pg/ml) 1 mg Hormone-free Figure 8: E2-Concentration during a 28-day administration regimen (Lu et al. 2007); average E2-level ("through-level") in daily oral • Rare side effects of E2V/DNG such as venous (VTE) or arterial thromboembolism (ATE) will have to be reassessed in a large-scale studies following the introduction of In this case, cycle control is acceptable because: the preparation to the market.
1. Estrogens dominate in the early menstrual cycle, which causes early endometrial proliferation and an increase in Consequently, the same contraindications for other com- sensitivity for progestin activity during mid-cycle.
bined oral contraceptive pills apply for E2V/DNG. E2V/DNG 2. Progestins dominate from mid-cycle onwards.This is therefore suitable for women of all age groups, but guarantees stability of the endometrial stroma (Hirvonen particularly for those who: et al. 1990; Kivinen and Saure 1996; Schubert and Cullberg • prefer natural estrogens 1987; Serup et al. 1979).
• wish to benefit from the antiandrogenic activity of dienogest (i.e. blemished skin, seborrhoea, acne) Downloaded from cme.akademos.de on Friday, October 7, 2016 A multicentred, randomized, double-blind study (E2V/DNG • wish to reduce the hormone-free interval (patients with Copyright 2016 akademos Wissenschaftsverlag. All rights reserved und EE/LNG) monitoring 7 menstrual cycles in 798 women menstrual cycle -dependent complaints such as dysmen- aged 18 to 35 years showed the following acceptable orrhea, pelvipathia spastica, menstrual migraine bleeding pattern:• shorter and weaker withdrawal bleedings with E2V/DNG compared to EE/LNG Non-oral combined formulations
• 20% of women per cycle without withdrawal bleedings with E2V/DNG, only 8% with EE/LNG • Number of irregular bleedings similar to a pill containing Transdermal contraception is available as the Evra® 20 μg EE/100 μg LNG (Ahrendt 2009; Ahrendt et al. 2009; transdermal contraceptive patch. The patch has a size of Parke et al. 2008) 4.5x4.5 cm and is applied to the skin once a week (alwayson the same weekday), preferably on the upper arm, the Studies concerning the influence on metabolic and rheo- trunk or the gluteus maximus. Three patches are followed logical activity demonstrated a positive effect on surrogate by a one-week interval.
parameters. However, clinical evaluation especially con-cerning thromboembolic events has to be interpreted as Evra® contains the progestin norelgestromin and the estrogen ethinylestradiol. Norelgestromin is the main • The risk for thomboembolic events due to E2V/DNG is still metabolite of norgestimate.
unknown, as only limited data from clinical trials is avail-able.
Ahrendt H.-J. Hormonal . Gynakol Geburtsmed Gynakol Endokrinol 2009; 5(2): 68–81 published 31.07.09 www.akademos.de/gyn akademos Wissenschaftsverlag 2009 ISSN 1614-8533 A daily dose of 150 μg norelgestromin and 20 μg ethinylest- In the vagina, a daily dose of 15 μg ethinylstradiol and 120 μg radiol is released, which leads to a constant serum hormone etonogestrel are released. After five days, the maximum level that causes complete ovulation inhibition. Contra- serum hormone level is attained, which then persists for ceptive safety is good (Pearl-Index: 0.70). Sauna, whirlpool the next three weeks.
or cold water do not alter the rate of hormonal absorption.
The NuvaRing® has a high contraceptive safety (Pearl- In terms of pharmacological interaction, the concurrent Index: 0.65). Its mode of action is based on complete administration of tetracyclines does not reduce contracep- tive safety of the patch. However, recent studies couldprove that the risk for thromboembolic complications is After discontinuation, ovulation quickly reenters.
2-fold higher than in the oral combined contraceptive pill (x instead of y/10 000 years of application), while it is re- The concurrent vaginal administration of spermicides and duced in hormone-replacement patches. The underlying antimycotics has no proven negative effect on the contra- reason is likely to be the continuous release of ethinylestra- ceptive safety of the vaginal ring, neither does the con- diol and its effect on the liver.
current oral administration of doxycyclin or amoxicillin.
Menstrual cycle pattern Three patches are followed by a patch-free week with Cycle control is excellent. The withdrawal bleedings occur withdrawal bleeding. Unscheduled bleedings within the regularly in every ring-free week.
first cycles occur more frequently compared to oral contra-ceptives. After three cycles, the occurrence corresponds to With an average of 5%, irregular bleeding is seldom com- that of the pill.
pared to the oral contraceptives. In contrast to the oralcontraceptives, the irregular bleedings do not occur within the first three cycles. The ring is recommended for patients Handling of the patch is user-friendly and it adheres re- experiencing recurrent irregular bleedings with oral contra- liably. In approximately 2% of cases, detachment occurs.
Compliance can sometimes be impaired by the occurringdirty edges. One adverse effect is skin irritation that can be found in 17.2% of cases. 94.5% of these local skin reactions Acceptance of the ring is high. The patient inserts and are mild to moderate. For 2% of the patients, this adverse removes the ring herself without difficulties.
effect is a reason to discontinue treatment.
Disturbing influence on sexuality are exceptions. Usually, women using the NuvaRing® and their partners are For vaginal contraception, a hormone-containing vaginal Downloaded from cme.akademos.de on Friday, October 7, 2016 ring, NuvaRing®, is available. The ring has a diameter of Copyright 2016 akademos Wissenschaftsverlag. All rights reserved 54 mm and a cross-section of 4 mm. It consists of the syn- Per day, the ring may remain three hours outside of the thetic medical material ethylene vinyl acetate (EVA). The vagina without impairing contraceptive safety. The ring can ring contains the progestin etonogestrel and the estrogen also remain in the vagina for an additional week without ethinylestradiol. Etonogestrel is the active metabolite of losing its effect. This can be important for the individual desogestrel. The ring remains in the vagina for a period of consultation of the women.
three weeks, which is followed by a one-week ring-freeinterval that induces withdrawal bleeding. After the ring- The NuvaRing® is suitable for long-term use, especially for free interval, a new ring is inserted.
three or four months. This has been proven by a randomi-zed study (Barreiros et al. 2007; Miller et al. 2005).
The ring is well tolerated. Undesired side effects such asmastodynia, vaginitis, nausea or headaches are rare. Thering has a neutral effect on weight gain (Ahrendt et al.
2006; Barreiros et al. 2007; Miller et al. 2005).
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• Advisory council for the mid-German society for gyneco- logy and obstetrics (Mitteldeutsche Gesellschaft für Gynäkologie und Geburtshilfe) • Advisory council for the German society for women's health (Deutsche Gesellschaft für Frauengesundheit) • Society for sexology (Gesellschaft für Sexualwissen- • Academy for sexology • Working group for hormonal contraception Prof. Dr. med. Hans-Joachim Ahrendt • Working group for climacteric syndrome• Working group for hormones of the professional Praxis für Frauenheilkunde association of gynecologists (Berufsverband der Klinische Forschung und Weiterbildung Halberstädter Straße 122 • Member of the panel of experts on sexual health (Expertengruppe sexuelle Gesundheit) Prof. Ahrendt is the representative chairman Saxony- Prof. Ahrendt works as a specialist for gynecology and Anhalt of the professional association of gynecologists obstetrics in his own practice, which has an adjacent day (Berufsverband der Frauenärzte e.V.) clinic. His focus lies on gynecologic endocrinology andsexual medicine. Apart from the clinical department, the Conflict of interest practice also includes a department for clinical research The author declares that there is no conflict of interest as and further education.
defined by the guidelines of the International Committeeof Medical Journal Editors (ICMJE; www.icmje.org).
Prof. Ahrendt studied medicine at the medical academy(now Otto-von-Guericke-University) in Magdeburg. After- Manuscript information wards, he continued working at the University Clinic for Submitted on: 24.06.2009 Gynecology in Magdeburg, where he completed his spe- Accepted on: 30.06.2009 cialization, his doctorate and his habilitation.
His professional and scientific interest was since focusedon hormonal contraception, endocrinology and sexualmedicine. In his habilitation, he studied sexual behaviourand contraception in teenagers. During this time, he estab-lished further education programmes in the sexual medi- Downloaded from cme.akademos.de on Friday, October 7, 2016 cine area and is a lecturer at the medical faculty of the Copyright 2016 akademos Wissenschaftsverlag. All rights reserved Otto-von-Guericke-University in Magdeburg.
His scientific focus are sociological studies concerningsocial, sexual and contraceptive behaviour as well as clini-cal studies particularly with regard to the development ofhormonal contraceptives, hormone replacement therapy,non-hormonal treatment of climacteric symptoms andlibido.
He has published more than 100 scientific and generalpapers and has held more than 400 scientific presenta-tions on symposia and congresses on the above-mentionedtopics.
Prof. Ahrendt is a member of the following medical-scientific associations and working groups:• German society for gynecology and obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe (DGGG)) • Society for gynecologic endocrinology and reproductive medicine (Gesellschaft für Gynäkologische Endokrinolo-gie und Reproduktionsmedizin) Ahrendt H.-J. Hormonal . Gynakol Geburtsmed Gynakol Endokrinol 2009; 5(2): 68–81 published 31.07.09 www.akademos.de/gyn akademos Wissenschaftsverlag 2009 ISSN 1614-8533 Question 6
How many mg estradiol (E2) are equivalent to 1 mg
estradiol valerate (E2V)? a. 1.00b. 0.94 Combined hormonal contraceptives
Question 7
Question 1
How many women suffer from premenstrual Which of the following is not an indication for hormonal contraceptives exerting antiandrogenic d. Lactatione. PCO syndrome Question 8
The 17α-ethinyl residue in ethinylestradiol causes:
Question 2
a. rapid metabolization The high contraceptive safety of oral hormonal b. slow metabolization contraceptives is not based on: c. a short half-life a. Inhibition of sperm ascent d. a reduced effect on the endometrium b. Impaired ovum transport in the fallopian tube e. poor cycle stability c. Increased FSH- and LH released. Inhibition of follicle maturation and ovulation Question 9
e. Inhibition of nidation in the endometrium The "dynamic" dose regimen in the combinationpreparations containing E2V and DNG is responsible Question 3
Which of the following statements concerning the a. superior cycle stability NuvaRing® is correct? b. frequently occurring irregular bleedings a. It contains the estrogen ethinylestradiol and the c. hypermenorrhea b. It is a progestin-only preparation.
e. premenstrual syndrome c. Its effect is exclusively due to a complete ovula- tion inhibition.
Question 10
Downloaded from cme.akademos.de on Friday, October 7, 2016 d. Hormone withdrawal bleeding regularly occurs in Abridgement of the hormone-free interval to only Copyright 2016 akademos Wissenschaftsverlag. All rights reserved every ring-free interval.
four days causes: e. The ring can be outside of the vagina for up to a. more severe menstrual migraine three days without impairing its effectiveness.
b. exacerbation of skin manifestations (seborrhoea, acne) Question 4
c. increased frequency of irregular bleedings Which of the following is not an indication for an d. improvement of the premenstrual syndrome extended-cycle regimen? e. exacerbation of dysmenorrhea a. Hypermenorrheab. Iron deficiency anaemiac. Breast cancer d. Premenstrual syndromee. Functional ovary cysts Question 5
Which of the following side effects of hormonal
contraceptives is estrogen-derived?
a. Hypermenorrhea
b. Uterine fibroid growth
c. Mastodynia
d. Depressive disorder
e. Headaches

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