Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive Medicine and Endocrinology –

Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie

Contraception - Update and Trends Rabe T J. Reproduktionsmed. Endokrinol 2010; 7 (Sonderheft 1), 18-38

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Contraception – Update and Trends*

T. Rabe

Fertility control in the future will focus on the improvement of existing methods (efficacy, side effects, easy use, duration of action, manufacturing process, costs), on new approaches (mode of action) bringing additional health benefits, and on new targets for nonhormonal contraception. Counselling of women in view to contraceptive choices based on the individual risk (e. g. cardiovascular disease, thrombophilia, family risk of breast cancer, sexually transmitted diseases) will gain more and more importance. Only a few companies can afford research in contraception such as Bayer-Schering-Pharma, and MSD. Female contraception: Ovulation inhibition: preselection of patients to minimize the individual risk. New oral contraceptive (OC) regimen, OC with new progestins, OC with or estradiol esters, new ovulation inhibitors with new progestins and new regimen including long cycles and continuous delivery of steroidal contraceptives, new contraceptive patches, vaginal rings andsprayon contraceptives. Recently identified genes involved in the ovulation process as new targets for ovulation inhibitors. Fertilisation inhibition: new intrauterine systems have been developed: a smaller Mirena intrauterine system releasing (LNG) and a new frameless progestinreleasing intrauterine systems (IUS). Various new contraceptive barri- ers have been introduced. Research is ongoing on substances acting both as and as microbicides as a dualprotection method reducing both the risk of unwanted pregnancy and the risk of sexually transmitted diseases. New implantable systems and improved injectables (with improved phar- macokinetic profile, decreased side effects and a safer delivery system) have been made available recently. Various new approaches in female sterilisation include non invasive method of tubal occlusion Immunocontraception for the female will not be available in the near future. Implantation inhibition: selective receptor modulators (SPRMs) are tested for ovulation suppression, morphological changes of endometrium surface inhibiting implantation, postcoital contraception and for longterm use and drug safety. Male contraception: and are the only meth- ods available for male contraception. The development of parenteral hormonal contraceptives for men has been stopped recently by the industry but other organizations continue the search for appropriate methods such as combinations of and progestin in implants and also transdermal gels STD: Furthermore clients of contraceptive methods must be informed about the risk of sexually transmitted diseases and the way how to prevent them (e. g. safer sex methods). J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1): 18–38. Key words: contraception, family planning, fertility control, female, male, ovulation, fertilisation, implantation, spermatogenesis

„ Introduction • Internet Links – United Nations Population Fund – UNFPA, the United Nations Population According to projections of the United Fund (http://www.unfpa.org) Nations (UN) and the World Bank, 80– – The world’s growing population [PDF] (http://wbln0018.worldbank.org/ 90 % of population growth until 2025 HDNet/hddocs.nsf/65538a343139acab85256cb70055e6ed/8ebf48e0f2ac will occur in developing countries; 50 % 79c385256e00005eb785/$FILE/Growing%20Population.pdf) of population growth is based on in- – WHO, Geneva, Switzerland (http://www.who.int/reproductivehealth/en) creasing life expectancy attributed to – The World at Six Billion United Nations – Introduction [PDF] e. g. better medical care, 17 % of couples (http://www.un.org/esa/population/publications/sixbillion/sixbilpart1.pdf) are wishing for more than two children – World population – Wikipedia, the free encyclopedia. Current projections by and 33 % of the population growth stems the UN’s Population Division (http://en.wikipedia.org/wiki/World_population) from unwanted pregnancies. – United Nations Statistics Division – Common Database Population annual growth rate, estimates and projections (annual, 1950 to 2050) The demand for fertility control is ex- (http://unstats.un.org/unsd/cdb/cdb_dict_xrxx.asp?def_code=379) pected to increase within the next two to three decades as the number of couples in the reproductive age groups in devel- convenience. Even in some developed oping countries alone is expected to „ Contraceptive Use and countries where contraception is freely grow to nearly 1 billion. The situation in Techniques available, many unplanned pregnancies most developed countries is quite differ- occur. There is thus a real need for new ent: e. g. in Germany, there is a ratio of The prevalence of contraceptive use is methods of contraception to be devel- 1.3 children per couple, which is far be- increasing worldwide, and in many oped that are more effective, easier to low the threshold value of 2.1 necessary countries over 75 % of couples use ef- use, and safer than existing methods. for maintenance of the population size fective methods. However, existing and to guarantee the retirement funds for methods of contraception are not perfect, Demographic forces, prevalence of dis- the elderly. do not fit all couples and their accept- ease, and social and cultural factors in- ability is limited by side effects and in- fluence not only the use of contracep-

* Updated version from: Rabe T. Contraception – Update and Trends. J Reproduktionsmed Endokrinol 2007; 4 (6): 337–57.

Received and accepted: July 29, 2010. From the Department of Gynecological Endocrinology and Reproductive Medicine, Medical School Heidelberg Germany Correspondence: Thomas Rabe, MD, PhD, MD (hons), Professor Obstetrics and Gynecology, Department of Gynecological Endocrinology and Reproductive Medicine, Univer- sity Women’s Hospital, Medical School Heidelberg, D-69115 Heidelberg, Voßstraße 9; e-mail: [email protected]

18 J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. Contraception – Update and Trends tives but also the development of new „ Research in the Field of Ovulation Inhibition methods. The age of onset of sexual ac- Contraception The release of the female germ cell, the tivity is decreasing, while childbearing ovum, from the ovary is a key event in is being delayed or, in many developed Research on new contraceptives is only mammalian reproduction. Ovulation is a countries, forgone altogether. There is done by Bayer-Schering-Pharma, and complex process that is initiated by the public pressure for the use of more Organon (now MSD); generics are luteinizing hormone surge and is con- “natural products”, which are perceived mainly produced by Barr Laboratories, trolled by the temporal and spatial ex- to be safer, but at the same time contra- US. To find one new substance more pression of specific genes. ceptives are expected to have almost per- than 5000 drugs need to be tested over fect efficacy. 10–15 years, costing 400–800 million Ovulation inhibition can be achieved by US Dollars. Both Wyeth, bought by oral hormonal contraceptives (100 mil- The development of new and improved Pfizer, and Ortho McNeil have stopped lion women worldwide) [2], hormonal methods of contraception for both the research in the field of contraception. patches (1 million users worldwide), women and men is a key component of vaginal rings (3 million users world- the strategy to improve the quality of According to the WHO (World Health wide), estrogenfree progestin formula- family planning programs. Family plan- Organisation, Geneva, Switzerland) fer- tions (2 million users worldwide), once- ning clients are often restricted by the tility control in the future will focus on a-month injectables (2 million users in choice of methods offered to them, or are [1]: Middle and South America), and pro- deterred from using contraception due to 1. Improvement of existing methods: longed breastfeeding (100 million the side effects related to use of available efficacy, side effects, duration of ac- women worldwide) (personal informa- methods. The crucial issues in the future tion, manufacturing process, costs tion Bayer-Schering-Pharma 2007 and will therefore be aimed at optimizing the 2. New approaches: more selective Organon 2007). use of currently available methods and mode of action making them safe, effective, and accept- 3. New targets for contraception Oral Hormonal Contraceptives able, with minor alterations in composi- Update tion or delivery system. In addition, In this paper, the authors will describe Oral hormonal contraceptives (combined there should be new developments in the actual knowledge on fertility control or sequential /progestin formu- contraceptive technology to improve and possible future aspects based on the lations) have been available since 1959 compliance and satisfy the unmet needs. various targets for contraception in (Enovid/Synthex/US) and as Anovlar women and men. (Schering/Germany) since 1961 (Europe). Contraceptive choices can be classified Composition: OCs contain either pro- according to their mode of action and the • Internet Link gestins derived from 19-nortestosterone duration of use (reversible and perma- – Family planning, contraception: as 1st (, norethisterone ac- nent methods). Guidelines, reviews, position pub- etate, , ethinodiol diacetate, lished by the Geneva Foundation 2nd (levonorgestrel) or 3rd generation (de- „ Requirement for New for Medical Education sogestrel, , ) or (http://www.gfmer.ch/Guidelines/ new nonethyl estranges with antiandro- Contraceptives Family_planning/Family_plan- genic properties (), derivatives The requirements for new contraceptives ning_contraception.htm) of 17-hydroxyprogesterone (e. g. chlor- include: madinone acetate, cyproterone acetate) – good contraceptive efficacy (female or spirolactone derivates with high anti- [f]/male [m]), „ Female Contraception mineralocorticoid properties (drospire- – good control of the (f), none) and 15–35 µg – no side effects (f/m), Contraceptive methods for women can (EE) per tablet. New generations of OCs

– reversible (f/m), be classified according to the inhibition containing Estradiol (E2) rather than EE – no negative effect on libido (f/m), of ovulation, fertilisation and implanta- are reaching the market and are based on – easy to use (f/m), tion, respectively. new progestins such as dienogest, or new – not expensive (f/m), 19-norprogesterone derivatives such as – worldwide availability (f/m), For some of the contraceptive methods a or (for oral use in – worldwide acceptable based on reli- Cochrane analysis is available. But this OCs) or Nestorone® (for nonoral use

gious, political, and ethical consider- analysis can only be as good as the un- combined with E2 in transdermal gels). ations (f/m), derlying studies are. Because of the im- Indication: Oral hormonal contracep- – offering “non contraceptive benefits” portance of placebocontrolled random- tives can be used for fertility control but (f/m) with increasing interest, e. g. ized trials that cannot be conducted for also for various medical reasons e.g. no influence on body weight (f/m), contraception purpose, most of these treatment of disturbances of the men- no risk for breast cancer (f) or pros- studies are open and must be carefully strual cycle, dysmenorrhoea, premen- tate cancer (m), positive effect on skin analysed in view to e. g. sample size, ori- strual syndrome (PMS) and acne vulgaris. and hair (f/m), no or decreased men- gin, selection, performance of the study, strual bleedings (f), improvement of dropouts and other bias – which may lead Acne vulgaris dysmenorrhoea (f), improvement of to wrong conclusions (e. g. Women’s In Germany there is a high incidence of premenstrual syndrome (f) Health Initiative Study). at least mild types of acne vulgaris and

J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) 19 Contraception – Update and Trends seborrhoe (40–60 % of all women aged patient history in view to cardiovascular tween groups where this was studied 15–25). events is important. (see also [9]).

OCs with antiandrogens (cyproterone The following laboratory tests for throm- Bone density and fractures [10] acetate, , dieno- bophilia can be performed if indicated: A higher BMD and a larger bone size gest, and ) are preferred by e. g. Factor V-Leiden gene, prothrombin attained in childhood and maintained more than 60 % of all women in the re- polymorphism, plasminogen activator through the third decade of life has been productive age (personal information inhibitor (PAI) polymorphism, anti- related to a subsequent reduction in the Bayer-Schering-Pharma, 2007), but mild thrombinIII, protein C, protein S, Factor risk of childhood fracture, stress frac- acne can also be improved by using vari- VIII, homocysteine, and if elevated ture, osteoporosis and fractures related ous oral contraceptives. In a Cochrane MTHFR gene (methyltetrahydrofolate to osteoporosis later in life. Therefore, it analysis [3], Arowojolu AO et al. found acid reductase). is important to understand factors that can 23 trials dealing with pills be modified to improve the accrual of peak and acne: 5 trials used ‘dummies’, 17 The individual risk in relation to throm- bone mass and increase the bone size in compared different types of birth control bophilia can be analysed and the patient women. Factors that may positively in- pills, and 1 compared a pill and an antibi- can be counselled with regard to the risk fluence BMD are high levels of physical otic. The three pills studied in trials with of contraception and lifestyle (e. g. activity and adequate calcium intake. dummies worked well to reduce facial longdistance travel). acne. In comparing pills with different Genetic factors account for 60–80 % of hormones, no important differences Side effects the variance in peak bone mass. Failure were seen. to achieve the genetically predetermined OC and body weight complement of bone mass is often related OC and brain The body weight is a very important fac- to suboptimal environmental and life- OC may lead to mood changes. Depres- tor for female self esteem and wellbeing. style conditions in women. Bone accrual sive mood and premenstrual syndrome can also be limited by eating disorders (PMS) occur quite frequently in various Various OCs lead to changes of the body and oligo and amenorrhea. Oral contra- female populations (incidence of mild weight in new users of plus/minus 1– ceptive (OC) use may have an effect on PMS 30–80 %; incidence of moderate 2 kg depending on e. g. the annual sea- bone accrual but its exact role is unclear. PMS 20–40 %). The incidence of the se- son the user starts the pill, the initial vere type of the disease, the premen- body weight, psychological factors etc. Oral contraceptives strual dysphoric disease (PMDS) is 2– There is some evidence attributing a 9 % [4–7]. The impact of OCs on the body weight modest benefit of oral contraceptive use doesn’t depend on anabolic effects; ste- to spine and hip BMD. Alternatively, Depressive mood occuring in patients roid hormones can enhance the appetite; several recent studies have shown either with premenstrual syndrome may improve ethinylestradiol may lead to water reten- no effect or negative effects of oral con- using oral contraceptives; an ex tended tion in soft tissue. traceptives on bone density. The impact cycle may offer some advantages, too. of OC on bone size is not well under- Drospirenone containing OCs may lead stood either. A 24 day regimen with drospirenone to a decrease of body weight in new us- called “YAZ” was approved in the US in ers by up to 0,5 kg in the first six months The type of contraception, age at first 2005 for the treatment of emotional and with an increase up to values observed use and level of exercise may alter the physical symptoms of premenstrual dys- with other OCs thereafter. However this impact of OC use on bone health. phoric disorder (PMDD), which is a se- weight change is related to water excre- vere form of premenstrual symptoms. In tion due to the antimineralocorticoid ef- Observational studies of OC use on bone Europe YAZ is available since 2008. fect of the progestins as compared with mass may be confounded by the underly- other OCs inducing water retention is ing reason for use as 4–9 % of women Depressive mood in OC users might be most users. use oral contraceptives for reasons other due to a deficiency of vitamine B6. than birth control, including amenorrhea In a Cochrane analysis Gallo et al. [8] or oligomenorrhea. Exclusion of risk factors found that contraceptives pills and patches do not lead to major weight gain. A recently published study of female Cardiovascular risk factors The 3 placebo-controlled, randomized military cadets has shown that the use of Family history in view to cardiovascular trials did not find evidence supporting a oral contraceptives is linked with loss of disease is gaining more and more impor- causal association between combination bone density in women. The study exam- tance, in view to find out women at risk. oral contraceptives or a combination ined the effects of lifestyle, diet, and ex- The family history includes deep vein skin patch and weight gain. Most com- ercise on bone health of 107 white fe- thrombosis, thromboembolism, cerebral parisons of different combination con- male cadets at the United States Military stroke in the parents (< 45 years), myo- traceptives showed no substantial differ- Academy in West Point, New York, and cardial infarction (mother < 45 years), ence in weight. In addition, discontinua- found that irregular menstruation and and any of these diseases in brothers and tion of combination contraceptives be- oral contraceptives had a negative im- sisters of the patient. Furthermore the cause of weight gain did not differ be- pact on bone density [10].

20 J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) Contraception – Update and Trends

In adolescents there is a slight diminish- used birth control pills, regardless of who had either used or never used OCs, ment of bone mineral density but no family history of breast cancer, re- comparing their mortality rates. The four higher fracture rate. Also this question productive history, geographic area decades of data showed that there was a must be clarified for OCs on the market of residence, ethnic background, dif- small decrease in the mortality rates of and for new products. ferences in study design, dose and women who had taken the pill, as well as type of hormone, or duration of use. a small decrease in the overall risk of Oral contraceptives and cancer – Course of disease: In addition, breast developing cancer. The authors con- A recent review dealing with hormonal cancers diagnosed in women after 10 cluded that oral contraception was not contraception and cancer in women has or more years of not using OCs were associated with an increased long-term been just published by [11]. A reprint of less advanced than breast cancers di- risk of death in this large UK cohort; in- this paper is also published in this agnosed in women who had never deed, a net benefit was apparent. The supplement. used OCs. balance of risks and benefits, however, – Excess number of cases: The breast may vary globally, depending on pat- Breast cancer cancer incidence in young women is terns of oral contraception usage and – Incidence: The incidence of breast low and rises steeply with age. The background risk of disease [16]. cancer is worldwide increasing; one estimated excess number of cancers of ten women will suffer from breast diagnosed in the period between Even in patients with high family history cancer during life time. starting use and 10 years after stop- risk for breast cancer and in carriers of ping increases with age at last use: BRCA1 mutation OC seem to have no Risk factors are analysed in various re- for example, among 10,000 OC users negative influence of the breast cancer views (e. g. [12], (http://info.cancerre from Europe or North America who incidence in those subjects [17, 18]. searchuk.org/cancerstats/types/breast/ used oral contraceptives from age 16 riskfactors). According to Fletcher [13]: to 29, the estimated excess number of The question why in OC users there is a – Strong risk factors are increasing age, cancers diagnosed up to 10 years af- higher detection rate of breast cancer family history, previous breast cancer. ter stopping use rises from 0.5–4.7. (earlier detection of preexisting tumours) – Moderate risk factors are density of or a higher life-time risk (additional new the breasts on mammogram, biopsy The Reanalysis by the Collaborative tumours in OC users) has not settled un- abnormalities, exposure to radiation. Group on Hormonal Factors in Breast til now. A stimulation of preexisting – Other risk factors: age at time of re- Cancer 1996 [14] is based on data with breast cancer is assumed, rather than in- productive events, pregnancy and older high-dose combined oral contra- duction of mutagenesis and new tumours breastfeeding, hormone replacement ceptives used between 1976 and 1996 (latency between exposition towards a therapy (HRT), height and weight, whereas today worldwide low-dose pills noxe and clinical detectable carcinoma: alcohol consumption, presence of are used. 10–15 years). other cancers, miscellaneous factors. – Decreasing the risk are removal of In a big casecontrol study Marchbanks et In postmenopausal women the lower in- the ovaries, lifestyle changes, medi- al. [15] interviewed a total of 4575 cidence of HRT use led recently to a lower cation, early detection. women with breast cancer and 4682 con- rate of breast cancer cases diagnosed. trols who were 35–64 years old. The A reanalysis of worldwide epidemio- relative risk was 1.0 (0.8–1.3) for Regular cancer screening including self logic data on the possible relationship women who were currently using oral examination of the breasts is strongly between OCs and the diagnosis of breast contraceptives and 0.9 (0.8–1.0) for recommended. cancer had been conducted 1996 by the those who had previously used them. Collaborative Group on Hormonal Fac- The relative risk did not increase consis- Ovarian cancer tors in Breast Cancer. The reanalysis in- tently with longer periods of use or with – Epidemiology: Second most frequent volved 54 studies (90 % of all epidemio- higher doses of estrogen. The results genital tumour of women in Germany. logical studies), a total of 53,297 women were similar among white and black – Incidence: New cases 15/100,000, with breast cancer and 100,239 women women. Use of oral contraceptives by maximum at age 50–60 years; age without breast cancer [14]. women with a family history of breast 45: 40/100,000; age 70: 50/100,000. Results of this reanalysis: cancer was not associated with an in- In 2 of all cases first diagnosis in – Breast cancer risk: Women who were creased risk of breast cancer, nor was the FIGO stage III and IV. current or recent users of birth con- initiation of oralcontraceptive use at a – Risk factors: High risk situation in trol pills had a slightly elevated risk young age. In conclusion among women cases with genetic predisposition of having breast cancer diagnosed. from 35–64 years of age, current or (BRCA1 and 2); approx. 10 % of all – Age and risk: The risk was highest former oralcontraceptive use was not as- cases. for women who started using OCs as sociated with a significantly increased teenagers. risk of breast cancer. According to the Holden Comprehen- – Risk after OC withdrawal: However, sive Cancer Center, Cancer Information 10 or more years after women More recently, the results of the Royal Service (2003): The risk factors that are stopped using OCs, their risk of de- College of General Practitioners Study known to increase the chance of devel- veloping breast cancer returned to in the UK were published. From 1968 to oping ovarian cancer are family history, the same level as if they had never 2007, the study followed 46,000 women hormone replacement therapy, talcum

J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) 21 Contraception – Update and Trends powder, fertility drugs, high fat diet. The – Low-dose formulations: Few data mation about HPV and cancer is avail- protective factors for ovarian cancer are: are available on the more recent, low- able at http://www.cancer.gov/cancer- oral contraceptives, childbearing and dose formulations. topics/factsheet/risk/HPV. breastfeeding, and hyster- – A published case-control study in the ectomy. US showed a 38 % lower risk for Further risk factors are chlamydia infec- women who took high estrogen and tion [27] and cigarette smoking [28]. Studies have consistently shown (National progestin pills and a 81 % lower risk Cancer Institute, US) (www.cancer.gov/ for those taking low levels of both An analysis by the International Agency cancertopics/factsheet/Risk/oralcontra- hormones [23]. for Research on Cancer (IARC) (2003) ceptives): – Genetic risk factors: OC use in found: – Duration of use: OCs reduce the risk women at increased risk of ovarian – An increased risk of cervical cancer of ovarian cancer. In an analysis of cancer due to BRCA1 and BRCA2 with longer use of OCs. Researchers 20 studies of OC use and ovarian genetic mutations has been studied. analyzed data from 28 studies that in- cancer, researchers from Harvard One study showed a reduction in cluded 12,531 women with cervical Medical School found that the risk of risk, but a more recent study showed cancer. ovarian cancer decreased with in- no effect [24, 25]. – The data suggested that the risk of creasing duration of OC use. Results cervical cancer may decrease after showed a 10 to 12 % decrease in risk Endometrial cancer OC use stops [29]. after 1 year of use, and approxi- A metaanalysis by the IACR (1999) in- – In another IARC report, data from mately a 50 % decrease after 5 years cluded three cohort and 16 casecontrol eight studies were combined to as- of use [19]. studies which addressed the relationship sess the effect of OC use on cervical – Amount or type of hormones in OCs: between use of combined oral contracep- cancer risk in HPVpositive women. One of the studies used in the tives and the risk for endometrial cancer. Researchers found a fourfold in- Harvard analysis, the Cancer and The results of these studies consistently crease in risk among women who had Steroid Hormone Study (CASH), show: used OCs for longer than 5 years. found that the reduction in ovarian – Risk reduction: The risk for endome- Risk was also increased among cancer risk was the same regardless trial cancer of women who have women who began using OCs before of the type or amount of estrogen or taken these pills is approximately age 20 and women who had used progestin in the pill [20]. A more re- halved. OCs within the past 5 years [30]. cent analysis of data from the CASH – Duration of use and persistence: The – The IARC is planning a study to re- study, however, indicated that OC reduction in risk is generally stronger analyze all data related to OC use and formulations with high levels of the longer the oral contraceptives are cervical cancer risk [26]. progestin reduced ovarian cancer used and persists for at least 10 years risk more than preparations with low after cessation of use. Regular cancer screening including cer- progestin levels [21]. In another re- – Low-dose formulations with new pro- vix cytology is strongly recommended. cent study, the Steroid Hormones and gestins: Few data are available on the Reproductions (SHARE) study, re- more recent, low-dose formulations. Liver cancer searchers investigated new, lower- Summary according a recent statement dose progestins that have varying an- Use of sequential oral contraceptives of the National Cancer Institute (US) drogenic properties (testosteronelike which were removed from the consumer (www.cancer.gov/cancertopics/factsheet/ effects). They found no difference in market in the 1970s was associated with Risk/oralcontraceptives): ovarian cancer risk between andro- an increased risk for endometrial cancer. – Several studies have found that OCs genic and nonandrogenic pills [22]. increase the risk of liver cancer in – IACR analysis (1999) (http://www. Cervical cancer populations usually considered low inchem.org/documents/iarc/vol72/ National Cancer Institute, US (www. risk, such as white women in the vol721.html): 4 cohort and 21 case- cancer.gov/cancertopics/factsheet/Risk/ United States and Europe who do not control studies addressed the rela- oralcontraceptives): have liver disease. In these studies, tionship between ovarian cancer and Increased risk: Evidence shows that women who used OCs for longer pe- use of combined oral contraceptives. longterm use of OCs (5 or more years) riods of time were found to be at in- – Duration of use: Overall, these stud- may be associated with an increased risk creased risk for liver cancer. ies show a consistent reduction in the of cancer of the cervix [26]. – However, OCs did not increase the risk for ovarian cancer with increas- risk of liver cancer in Asian and Afri- ing duration of use. The reduction is HPV as main risk factor: although OC can women, who are considered high about 50 % for women who have use may increase the risk of cervical can- risk for this disease. Researchers be- used the preparations for at least five cer, human papillomavirus (HPV) is rec- lieve this is because other risk fac- years, and the reduction seems to ognized as the major cause of this dis- tors, such as hepatitis infection, out- persist for at least 10–15 years after ease. Approximately 14 types of HPV weigh the effect of OCs [31]. use has ceased. have been identified as having the poten- – Histology: A reduction in risk for tial to cause cancer, and HPVs have been Various cancer risks ovarian tumours of borderline malig- found in 99 % of cervical cancer biopsy A recent online publication in the British nancy is also observed. specimens worldwide [26]. More infor- Medical Journal by Hannaford [32] is

22 J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) Contraception – Update and Trends concerned with the overall cancer risk of gestrel-only pill. After several sence of bleeding has been reported oral contraceptives. Taking the contra- months the number of irregular [38]. Nevertheless the high rate of ceptive pill does not increase a woman’s bleedings in the -only intermenstrual bleedings and a chances of developing cancer and may group decreased [35]. Cerazette can higher pearl index when compared to even reduce the risk for most women. also be used by breast feeding combined oral contraceptives did not This is the conclusion of researchers women and can be used as normal led to a European approval of Lybrel. who analysed the UK cohort data span- oral contraceptive with a delay up to Ongoing studies are investigating the ning a 36-year period from the Royal 12 hours if somebody forget the contraceptive efficacy, the clinical College of General Practitioners’ oral regular intake of the pill. The major tolerability and the control of the contraception study, which began in disadvantages are continuous and menstrual cycle by a product called 1968. The accompanying editorial by unpredictable irregular bleedings in Yaz flex, developed by Bayer- Meirik and Farley [33] makes the point some of the women. Schering-Pharma. that in a developed country with an ef- – Extended cycle: An increasing num- fective cervical cancer-screening pro- Regimen of oral contraceptives ber of women are using OCs as long gramme, the pill is a safe contraceptive – Biphasic vs monophasic oral contra- cycle (3, 6 or more blisters of a con- method with respect to cancer. In some ceptives: in a Cochrane analysis tinuous combined OC without an OC developing countries with inadequate van Vliet et al. [36] did not find free interval). Patients must be in- cervical cancer screening and healthcare enough evidence to say if 2-phase formed that the extended cycle is an services, and high cervical cancer rates pills worked any better than 1-phase off-label recommendation. Further- the balance of cancer risk is probably types for birth control, bleeding pat- more they have to be informed about less favourable. terns, or staying on the pill. The one the management of break-through trial report had method problems and bleedings and withdrawal bleedings. Reduction of ethinyl estradiol dosage lacked data on pregnancies. There- If a regular control bleeding occurs, – Lowering the ethinyl estradiol (EE) fore, one-phase pills are the better the extended cycle must be stopped dosage per tablet from 50 to 30– choice, since we have much more and after a pill-free interval a new 35 µg led to a reduction of myo- evidence for such pills and two-phase extended cycle can be started. cardial infarction, stroke and deep pills have no clear reason for use. vein thrombosis (DVT). (Author’s comment: weak Cochrane In a Cochrane analysis of Edelman et al. – Lowering the ethinyl estradiol (EE) analyis due to lack of data). [39] oral contraceptives taken continu- dosage per tablet from 30–35 to 0 µg – Biphasic vs triphasic oral contracep- ously for more than 28 days compare fa- per tablet led only to a further reduc- tives: in a Cochrane analysis [37] vorably to traditional cyclic oral contra- tion of DVT. showed that available trials did not ceptives. 6 randomized controlled trials – Lowdose pills (20 µg versus > 20 µg provide enough evidence to say if met our inclusion criteria. Study find- ethininylestradiol/tablet) [34]: In this 3-phase pills worked any better than ings were similar between 28-day and Cochrane analysis the studies found 2-phase types for birth control, extended cycles in regard to contracep- that more women taking the pills bleeding patterns, or staying on the tive efficacy (i. e., pregnancy rates) and with less estrogen quit the studies pill. More research would be needed safety profiles. When compliance was early and that they had more disrup- to show whether 3-phase pills were reported, no difference between 28-day tions to bleeding patterns than the better than 2-phase pills. However, and extended cycles was found. Partici- women using the pills with more es- 2-phase pills are not used enough to pants reported high satisfaction with trogen. This review was not able to justify further research. (Author’s both dosing regimens, but this was not study differences in the low-estrogen Comment: weak Cochrane analyis an outcome universally studied. Overall pill ability to prevent pregnancy. due to lack of data). discontinuation and discontinuation for – Estrogen-free contraceptives: – Continuous daily regimen for 3 bleeding problems were not uniformly (Cerazette; MSD): Apart from induc- months: In the US two 3-months pill higher in either group in most studies. ing a local barrier, an estrogen-free are available: Seasonale (84 days The few studies that reported menstrual contraceptive in addition reliably 30 µg ethinylestradiol/150 µg levo- symptoms found that the extended cycle suppresses ovulation. Ovulation was )/7 days hormone-free. group fared better in terms of headaches, inhibited in 97 % of cycles at 7 and Seasonique (84 days 30 µg ethinyles- genital irritation, tiredness, bloating, and 12 months after initiation. The Pearl tradiol/150 µg levonorgestrel)/7 days menstrual pain. Five out of the six stud- Index was 0.14 per 100 woman 10 µg ethinylestradiol. ies found that bleeding patterns were ei- years, which is significantly lower – Continuous daily regimen: In 2007 ther equivalent between groups or im- than a pearl index of 1.17 found for the U.S. Food and Drug Administra- proved with continuous-dosing regi- levonorgestrel-only pill. Pearl indi- tion (FDA) approved Lybrel (90 µg mens. Endometrial lining assessments ces of the desogestrel POP and of levonorgestrel/20 µg ethinylestradiol by ultrasound were done in a small num- COC have not been compared di- tablets) (WyethAyerst) for a low- ber of participants but all endometrial rectly. At begin of the treatment there dose, continuous, non-cyclic combi- stripe measurements were less than was a higher incidence of amenor- nation oral contraceptive. In clinical 5 mm. rhoea and irregular bleedings in the trials (n = 2134) performed by the group receiving the desogestrel-only Conrad Programm (US) (2006) a Nevertheless, there is a great experience pill when compared to the levonor- pearl index of 1,26 and in 79 % ab- in Germany with extended cycles, a

J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) 23 Contraception – Update and Trends method which is highly accepted by pa- bleedings and a significant reductions in tients and doctors. The use of this regi- the duration of withdrawal bleeding per men in Germany is “off-label” and the cycle compared with EE/LNG [48]. Sig- patients must be informed. nificantly more patients per cycle expe- rienced absent withdrawal bleeding, According to a German study of the Bun- although only in a minority of cycles. deszentrale für gesundheitliche Aufklä- The efficacy of E2V/DNG for the treat- rung (BZgA) [40] 42 % of all German ment of heavy, prolonged and/or fre- women prefer regular menstrual bleed- quent menstrual bleeding without or- ings. ganic cause, measured by using the alka- line haematin method, has been investi- Trends gated in two identically designed double- Ethinylestradiol free contraceptives blind, randomised, placebo-controlled using estradiol or estradiol esters trials in USA/Canada [49] and Europe/ Figure 1: Spray-on contraceptive. From JRE 2007; 4(6): 337–57. Reprint with permission from “Museum für Over the years, changes made to com- Australia [50]. Together, the 2 studies Verhütung und Schwangerschaftsabbruch”, Wien, bined oral contraceptives (OCs) have provide the first evidence from rigorous www.muvs.org. focused on improving their tolerability randomised trials that an oral contracep- by reducing the dose of tive is an effective treatment for HMB. ovary must undergo a series of closely and ethinylestradiol (EE), modifying the Study results revealed a rapid effect of regulated events; each of them may be dosing regimen and incorporating pro- E2V/DNG, with a significant reduction targets of new substances suitable for gestogens with more favorable clinical in MBL seen from cycle 2 onwards. ovulation inhibition. Small follicles profiles. Additional efforts to improve E2V/DNG has been available in multiple must mature to the preovulatory stage, the acceptability of combined OCs have countries in Europe since May 2009, and during which the oocyte, granulosa cells, included the replacement of EE with is also available outside of Europe and in and theca cells acquire specific func-

17beta-estradiol (E2). In several historic the USA. tional characteristics. Theca cells begin clinical trials, E2-containing OCs have to synthesize increasing amounts of an- been found to provide effective contra- In the near future a new regimen with drogens that serve as substrates for the ception, but their association with unsat- natural (estradiol) in combina- aromatase enzyme in the granulosa cells, isfactory bleeding profiles has largely tion with nomegestrol acetate (Organon, granulosa cells acquire the ability to pro- prevented them from being developed Schering-Plough now MSD) will be duce estrogens and respond to luteiniz- further [41–43], (E2V) available. ing hormone (LH) via the LH receptor is promptly hydrolyzed to E2 after oral and the oocyte becomes competent to administration, and is identical to E2 in Research undergo meiosis. The sequence of tem- terms of pharmacodynamics and phar- Other targets for oral contraceptives in- poral events that occur during ovulation macokinetics [44]. An OC containing clude the development of estrogen-free is initiated in a responsive preovulatory estradiol valerate (E2V) and dienogest contraceptives. Clinical trials are ongo- follicle by a surge of LH, which impacts (DNG), an established that ing for sprayon contraceptives (Fig. 1). both theca and granulosa cells to stimu- was selected for its strong endometrial late cAMP and activate selective protein effects, in addition to its antiandrogenic New patents have been published in rela- kinase signalling cascades. These signal- properties and lack of androgenic activ- tion to progestins with antihistaminic ac- ling pathways rapidly induce transcrip- ity [45, 46] has been developed. These tivity, progestins with additional sulfa- tion of specific genes, which are ex- properties have enabled E2V/DNG to be tase-inhibition, androgen receptor mo- pressed transiently prior to follicle rup- the first E2-based COC that delivers dulators, and progesterone receptor mo- ture. The induced products initiate or al- natural E2 and provides effective cycle dulators. ter additional cell signalling cascades, control. E2V/DNG utilises dynamic dos- such as protease-driven cascades, which ing in a simple and continuous 1-pill- Furthermore new progestins are tested cause follicular rupture and promote fol- per-day format, which delivers an estro- for contraception (e. g. nomegestrol ace- licular remodelling to form a corpus lu- gen step-down, progestogen step-up tate, nestorone, ) which can teum. Remarkably, many events are spa- regimen over 26 days of active treat- be used for oral contraceptives, vaginal tially restricted to specific microenvi- ment, 2 days of placebo. This regimen rings, transdermal contraception via ronments within the follicle or surround- was designed to ensure good cycle con- patches or gel and for hormone replace- ing interstitial compartments to allow trol by maintaining estrogen dominance ment therapy (HRT). successful expulsion of the cumulus-oo- in the early part of the cycle and pro- cyte complex from the ruptured follicle gestogen dominance in the mid-to-late Research focuses on recent endocrine, [51]. part of the cycle. It also provides stable biochemical, and genetic information trough E2 levels over the whole 28-day that has been derived largely from the There is a special interest in leukotriene cycle, with low variability in E2 levels identification of newly identified genes inhibitors, new inhibitors of inflamma- over 24 hours [47]. Clinical trial data expressed in the ovary, and from knowl- tory-like response, prostaglandins [51]. show that E2V/DNG effectively inhibits edge gained by the targeted deletion of Furthermore folliculogenesis and ovula- ovulation [42] and offers women an ac- genes that appear to impact the ovulation tion can be blocked via specific inhibi- ceptable bleeding profile, with lighter process. To prepare for ovulation, the tors of follicle stimulating hormone

24 J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) Contraception – Update and Trends

(FSH) secretion, and inhibition of bind- Combination injectable contraception is ing of FSH and luteinizing hormone a highly effective, reversible method for (LH) to receptors; meiose inhibitor fac- preventing pregnancy. More women tor and inhibitors of meiose-activating using combination injectable contracep- compounds, MPF (maturation-promot- tives had regular (cyclical) bleeding pat- ing factor), OMI (oocyte maturation in- terns than those using progestinonly hibitor) [52, 53]. Research is ongoing for injectables. Also, fewer women using new OC formulations with addition of combination injectables stopped using cardioprotective agents. In view to mini- them because of bleeding reasons than mize the cardiovascular risk, especially progestin-only users. However, combi- Figure 2: Uniject: the subcutaneous DMPA formulation for the perimenopausal women new nation injectable users were more likely will be available as a single-use syringe. From JRE guidelines are necessary to improve the to discontinue for other reasons. While 2007; 4(6): 337–57. Reproduced with permission. Copy- contraceptive safety. stopping use can be viewed as a measure right Program for Appropriate Technology in Health (PATH). All rights reserved. of acceptability of the method, these re- • Internet Links sults should be considered with caution. events were headache, nausea, painful – Guidelines for prescribing com- Acceptability depends on many factors. periods, and abdominal pain, and the re- bined oral contraceptives. The new ports of these adverse events were simi- studies confirm that low dose com- Trends lar in the two study groups. bined oral contraceptives carry an A selfinjectable (Uniject/PATH) with extremely low. (http://bmj.bmj jour- the same content like Lunelle is cur- Trends nals.com/cgi/content/full/312/ rently in development (Fig. 2). A smaller patch releasing ethinylestradiol 7023/121/a) and gestodene (brand name: Fidencia/ – Peters MW, Pursley JR, Smith Bayer-Schering-Pharma, Germany) will GW. Inhibition of intrafollicular Update be available in the next years (Fig. 3). PGE2 synthesis and ovulation fol- Evra (Ortho-MacNeil), a contraceptive lowing ultrasoundmediated intra- patch releasing 150 µg Vaginal Ring follicular injection of the selective and 20 µg ethinylestradiol daily, was Update cyclooxygenase2 inhibitor NS398 first approved by the FDA/US in 2001 The vaginal administration of contracep- in cattle. J Anim Sci 2004; 82: (Fig. 3). The patch is applied weekly for tive steroids allows excellent cycle con- 1656–62. (http://jas.fass.org/cgi/ three consecutive weeks and followed by trol at much lower levels of total steroid content/full/82/6/1656) one week without patch. The FDA ap- exposure. – Oral Contraceptive Prescribing: proved updated labeling for the Evra Should Body Weight Influence contraceptive patch (November 10, Several vaginal rings have been devel- Choice of Pill? (http://www.contra- 2005) to warn health care providers and oped in the past (levonorgestrel ring by ceptiononline.org/contrareport/ patients that this product exposes the WHO, progesteronereleasing ring by article01.cfm?art=261) women to higher levels of estrogen than the Population Council). – New product review: desogestrel- most birth control pills. Women who use only pill (Cerazette) (2003) Evra are exposed to about 60 % more to- Finally, until now only the NuvaRing® (http://www.ffprhc.org.uk/pdfs/ tal estrogen in their blood than taking a (MSD) (made of ethylenevinylacetate Cerazette%20CEC%20Approved% typical birth control pill containing copolymer, releasing 15 µg ethinylestra- 2029.04.03.pdf) 35 µg of estrogen (FDA Updates Label- diol and 120 µg ) is avail- ing for Ortho Evra Contraceptive Patch able in most countries of the world and Once-a-Month Injectables 2005). highly accepted (Fig. 4). NuvaRing® is a Update unique delivery system that releases pro- Different brands of once-a-month inject- In a Cochrane analysis Gallo et al. [54] gestin and estrogen continuously for 3 ables are still available in Middle and compared the skin patch and vaginal ring weeks so that is used just once-a-month. South America (e. g. Mesigyna/Bayer- versus combined oral contraceptives. NuvaRing® is easy to insert and to re- Schering-Pharma). Lunelle (25 mg me- Three randomized controlled trials com- move and offers hormone delivery that is droxyprogesterone acetate and 5 mg es- paring the combination contraceptive more stable than a daily pill but just ef- tradiol cypionate given every 28 to 33 patch to a combination oral contracep- fective as the pill. Despite of the low es- days) were approved by the FDA in 2000 tive were found. The trials found that the trogen level, NuvaRing® offers a stable but production was stopped due to prob- two methods had similar pregnancy cyclus from the beginning. lems in manufacturing. rates. One trial found that patch users were more likely than oral contraceptive This ring is inserted on any day from day In the Cochrane analysis Gallo et al. [54] users to discontinue early from the trial, 1 to day 5 of a menstrual cycle for 21 analysed combination injectable contra- but a second trial did not find any differ- days, thereafter removed for 7 days ring- ceptives and found that combination in- ences in discontinuation between the free period and discarded. jectable contraception results in fewer groups. Women using the patch reported bleeding disruptions and fewer women breast discomfort more often than the Complete inhibition of ovulation is stopping use for bleeding reasons than women using the oral contraceptive. The observed during treatment with this progestinonly injectable contraception. remaining commonly reported adverse device. Clinical exposure to NuvaRing®

26 J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) Contraception – Update and Trends

sis of has been intro- duced in the European market which is licensed to be used up to 5 days after un- protected intercourse. The WHO has un- Figure 3: Contraceptive dertaken research in this area for the past patches: Left: Evra (Ortho- ten years, and our results are helping to McNeil). Right: Fidencia improve the safety, efficacy, acceptabil- (Bayer-Schering-Pharma). From JRE 2007; 4 (6): 337–57. ity, and ease of service delivery of emer- Reprint with permission from gency contraceptive methods. Bayer-Schering-Pharma In a Cochrane analysis Cheng et al. [56] analyse interventions for . Levonorgestrel and mife- pristone, the latter of which is only regis- tered and available as an emergency con- Figure 4: Left: NuvaRing® traceptive in China (in doses of 10 mg (Organon). Reprint with per- and 25 mg) and used off label in a lim- mission. Right: Nestorone® vaginal ring. From JRE 2007; ited number of other countries, are very 4(6): 337–57. Reprint with per- effective with few adverse effects, and mission: photo of Nestorone® are preferred to estrogen and progesto- Vaginal Ring © 2007, The Population Council, Inc. gen combined. Levonorgestrel could be used in a single dose (1.5 mg) instead of two split doses (0.75 mg) 12 hours apart. for 1786 women-years has resulted in Other vaginal rings in preclinical and might delay the following 21 pregnancies, giving a Pearl-Index of clinical trials releasing contraceptive menstruation. Women need to be in- 1.18. Withdrawal bleeding (4.7–5.3 steroids and/or microbicides are in de- formed about this to avoid anxiety. An- days) is regular (97–99 % of cycles) velopment. Preclinical studies must other effective method for emergency with rare incidence of irregular bleeding show if progesterone, antiprogestins, contraception is the IUD and it can be (2.6–6.4 %). The cycle control is good progesterone receptor modulators, estro- kept for ongoing contraception. with the use of this combined contracep- gens, antiestrogens, estrogen receptor tive vaginal ring. NuvaRing® is well tol- modulators (SERMS) can be used for Trends erated and accepted by women as com- transvaginal contraception. There is a special focus on new retro- pared to oral pill (s. review [55]). grade contraceptives (emergency contra- • Internet Links ceptive) which can be used after unpro- Trends – Population Council Projects: tected intercourse (progestins, antipro- New vaginal rings containing nomeges- Vaginal Ring (http://www.pop- gestins, selective progesterone receptor trol are under way (special indication: council.org/biomed/femalecon- modulators, postcoital insertion of cop- for lactating women). tras.html) perbearing T 380A IUD (Paragard). – Safety and Efficacy of a Contra- Clinical trials of a vaginal ring releasing ceptive Vaginal Ring Delivering WHO research is also under way on the 150 µg of nestorone (NES) and 15 µg of Nestorone® and Ethinyl Estradiol; use of as a possible method ethinylestradiol (EE) daily over the Study report published by Clini- of emergency contraception, and other course of a year were performed by the calTrials.gov (http://clinicaltrials. studies are being undertaken on the ef- Population Council (New York/US) and gov/ct/show/NCT00263341?order fectiveness of the IUD for use in emer- the Department of Reproductive Health =8) gency contraception. Further initiatives and Research of the WHO (through its are investigating the possible mecha- HRP program) (Fig. 4). Nestorone is a Emergency Contraception nisms of action of emergency contracep- potent, nonandrogenic, 19-norprogeste- Update tives. rone derivative, which is not active when Emergency contraception is using a drug given orally, but is highly active when or (IUD) to prevent Selective modulators of progesterone re- delivered via non-oral delivery systems, pregnancy after unprotected sex. This is ceptors (SPRMs), including antiproges- such as implants or transdermal prepara- for backup, not regular contraception. tins and PRMs with partial agonistic ac- tions. The high potency of nestorone tivities, look very promising in emer- makes it an excellent candidate for use in Postcoital pills are available worldwide, gency contraception since they are effi- contraceptive delivery systems designed in some countries as over-the-counter cient longer than levonorgestrel (120 h to be effective for prolonged periods. pill free of prescription. A onetime use for ulipristal acetate vs 72 h for levonor- The NES/EE vaginal ring is a longacting of levonorgestrel (1500 µg in one tablet gestrel). The clinically relevant mode of contraceptive device, but, unlike other or in two tablets each containing 750 µg) action of these substances is, like with longterm methods, its use is controlled up to 3 days after unprotected sexual ex- levonorgestrel, the delay or inhibition of by the woman without the need for medi- posure is mostly used. Recently a new ovulation. The difference is that those cal intervention. emergency contraception pill on the ba- substances may be able to be taken later

J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) 27 Contraception – Update and Trends up until shortly before the LH peak. The tion in both the amount and duration SPRM ulipristal has been able to show of menstrual bleeding, and alleviates that it is still efficacious at a time when menorrhagia/heavy menstrual bleeding the LH levels have already started to (HMB) and dysmenorrhea. The efficacy rise, thus increasing the chance to still of Mirena in the treatment of HMB has intervene at a moment when the risk of been compared to both other medica- conception is at its peak [57]. Clinical tions and to surgery: Mirena is superior trials have demonstrated a significantly to conventional medical therapy in the improved effect on the prevention of un- Figure 5: Levonorgestrel-releasing intrauterine sys- treatment of HMB, and is therefore rec- wanted pregnancies. Ulipristal acetate tems: Left: Mirena®; Right: “Small Mirena®”. From JRE ommended as the firstline treatment for 30 mg (marketed as ellaOne®) has al- 2007; 4(6): 337–57. Reprint with permission from Bayer- HMB by international guidelines [60]. ready reached the European approval Schering-Pharma The efficacy of Mirena is similar to that and is on the market in Europe. It is ex- of endometrial ablation, as confirmed by pected to reach the US market in 2011 years. The risk of infertility in women a recent metaanalysis [61]. Compared to [58]. not on risk for sexually transmitted dis- hysterectomy, treatment with Mirena re- ease seems to be low. sults in equal improvement of health-re- • Internet Link lated quality of life, even in long-term – WHO information sheet for emer- In a Cochrane analysis Kulier et al. [59] studies [62]. gency contraception (http.//www. showed that devices containing higher who.int/reproductivehealth/ dose of copper are more effective in pre- Due to its strong, localized progestoge- family_planning/docs/ec_fact- venting pregnancy over a longer time nic effect on the endometrium, Mirena® sheet.pdf) period (up to 12 years). Those devices has also been studied for prevention of may have more side effects, such as endometrial hyperplasia during ERT in Inhibition of Fertilisation bleeding, in the first 2 years, but are peri- and post-menopausal women, and Inhibition of fertilisation can be per- similar after that. Mirena® is approved for this indication formed by intrauterine devices (inert or in many countries. drug-loaded IUDs with copper or pro- Levonorgestrel-releasing system: The gestins), depot injectables, implantables, Mirena® levonorgestrel-releasing intra- The initial months of use of Mirena® are mechanical methods (diaphragm, portio uterine system belongs to the group of associated with irregular bleeding and caps), , behavioural meth- medicated IUDs releasing levonorges- spotting, which is followed by reduction ods, and surgical methods (tubal liga- trel intrauterine over a period of up to 5 of menstrual bleeding and oligo-amen- tion). Immunocontraception focussing years (Fig. 5). Additional non-contra- orrhea. The initial irregular bleeding/ on surface antigens of the oocyte and ceptive benefits are a lower rate of PID, spotting should be always taken into ac- sperm antigens are in preclinical studies. dysmenorrhoea, lower menstrual blood count in patient councelling, to avoid flow, shorter duration of menstruation, unnecessary removals. Intrauterine Devices (IUD) and decrease of bleeding episodes in Update patients with menorrhagia. Furthermore Frameless IUDs: The frameless copper- The first generation of IUDs consists of 20 % of all users will experience an releasing GyneFix is still not widely inert plastic material. The second gen- amenorhoea during the first 5 years of used. In a Cochrane analysis O’Brien eration are medicated IUDs, loaded Mirena® use, and up to 60 % when using and Marfleet [63] compared frameless either with copper or progestins. The the second Mirena®. The contraceptive versus classical intrauterine devices for most commonly used intrauterine de- effects of Mirena® are based on mainly contraception. The frameless IUD per- vices (IUDs) (or coils) are made up of a local actions of levonorgestrel (LNG) in forms similarly to traditional IUDs but T-shaped or horseshoe-shaped frame the uterus: thickening of cervical mucus, does not reduce bleeding and pain asso- surrounded by thin copper wires. The inhibition of sperm motility and func- ciated with standard IUDs. Traditional amount of wiring determines the ‘dose’ tion, and prevention of endometrial intrauterine devices (IUD) with plastic of a device. growth. In addition, some women expe- frames have side effects such as exces- rience suppression of ovulation, al- sive bleeding and pain that were thought Copper releasing IUDs: Today, medi- though after the first year, mos cycles are to be due to the frame. This review found cated IUDs releasing copper are accepted ovulatory. Based on these mechanisms, that symptoms of bleeding and pain, and worldwide (e. g. NovaT, Multiload 375). Mirena provides high contraceptive reli- contraceptive efficacy were not im- The primary mechanism of contracep- ability: the failure rate of Mirena is ap- proved with the frameless device. Trials tive action of copper IUDs is believed to proximately 0.2 % at 1 year and a cumu- are needed to see if the frameless IUDs be a prefertilization effect, interfering lative failure rate of approximately could benefit women who have not had with the passage of sperm through the 0.7 % at 5 years. This contraceptive effi- children. uterus but there is some evidence sug- cacy is comparable to that of female ster- gesting that there could also be a post- ilization, with full reversibility of fertil- Trends fertilization effect. Whereas the e. g. ity upon removal. New intrauterine devices under develop- Multiload 375 and NovaT can be used up ment are: Swing: copper-releasing with to 5 years other copper IUDs (not avail- In addition to its contraceptive action, coil stem; IUD releasing a progesterone able in germany) can be used up to 10 Mirena® also leads to a significant reduc- receptor modulator (CDB2914); Copper

28 J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) Contraception – Update and Trends

vagina over the cervix with the intention to block sperm. It is used in conjunction with spermicide. Lea’s Shield most strongly differs from other female bar- rier methods such as the and diaphragm because it exists only in one Figure 6: New diaphragms size (does not need to be specifically fit- and cervical caps. From ted to each woman). It stays in place be- JRE 2007; 4(6): 337–57. Upper row: SILCS (left). Re- cause of suction and it has a valve (cre- produced with permission. ation of suction, passage of cervical flu- Copyright Program for Ap- ids) (Fig. 6). propriate Technology in Health (PATH). All rights re- served. Lea’s Shield (right); The Prentif Cervical Cap (Rubber/ reprint with permission. latex, sizes 22, 25, 28, 31 mm). was a Lower row: FemCap (left); reprint with permission. popular cervical cap which is no longer Oves (right); reprint with available in the US but its still in use in permission © 2007 Ibis Re- other countries (e. g. UK). productive Health, Cour- tesy of Photoshare. The Oves Cervical Cap is a disposable cap, made of hypoallergenic silicone IUD releasing indomethacin or other to 2 hours before sex because spermicide which can be worn up to 72 h (Fig. 6). prostaglandin synthetase blockers or in- in only effective for 2 hours. hibitors [1]. A new model is the FemCap made of a Different types of latex diaphragms nonallergenic, durable silicone material, A smaller Mirena® intrauterine system are available (Allflex Arcing Spring, coming in three sizes. The FemCap is releasing LNG for a period of up to 3 Reflexions Flat Spring, Ortho Coil placed over the cervix and is partially years is under way by Bayer-Schering- Spring in different sizes from 55 to filled with contraceptive jelly or cream Pharma, Germany (Fig. 5). 95 mm in 5 mm steps, Practice Dia- (Fig. 6). phragm). Furthermore there are nonlatex A new frameless progestin-releasing diaphragms such as Milex Silicone Dia- In a Cochrane analysis Gallo et al. [65] IUS is also under way. phragm Omniflex, Milex Silicone Dia- found that the Prentif Cap worked as well phragm Arcing Style in sizes from 60 to as the diaphragm to prevent pregnancy. The use of antiprogestin in steroid-re- 90 mm in 5 mm steps. A Cochrane analy- The FemCap did not prevent pregnancy leasing intrauterine systems cannot yet sis [64] found that there is not enough as well as the diaphragm. Both cervical be evaluated. evidence about the effects of using a dia- caps appear to be medically safe. phragm without a spermicide, but it may Barrier Methods increase unwanted pregnancies. Trends Update New cervical caps on the market make re- Diaphragms and portio caps must be SILCS (silicone device placed in the va- moval easier compared to older models. used in combination with spermicides. gina to cover the cervix), a new dia- The cervical cap has a use effectiveness phragm is in development: It has “grip Hormonal Implants (Tab. 1) of about 82 % for nulliparous women dimples” on the sides of the rim, and its Update and 64 % for parous women, whereas shape makes insertion and removal easy An implant is a small flexible rod or a the method effectiveness is about 91 % (Fig. 6). capsule placed just under the skin in the and 82 % for nulliparous and parous upper arm. The Population Council, a women, respectively. Cervical caps: The cervical cap is a cer- nonprofit organization located in New vical barrier type of birth control. It fits York, began researching subdermal con- Diaphragm: The diaphragm is a thin snugly over the cervix and blocks sperm traceptive implants in 1966. Progesta- rubber dome with a springy and flexible from entering the female reproductive tional agents include , rim. It is inserted into the vagina, fits tract. Cervical caps may be made out of norethindrone, norgestrinone, and levo- over the cervix and is held in place by latex or silicone. norgestrel. The Food and Drug Adminis- vaginal muscles. A diaphragm holds tration (FDA) approved subdermal con- spermicide in place over the cervix. Dumas: Rubber/latex, sizes 1, 2, 3, 4, 5 traceptive implants delivering levonor- After intercourse, it should be left in gestrel in 1990. place for 6–8 hours. Diaphragms are 86– Vimule: Rubber/latex, sizes 1, 2, 3 94 % effective as birth control. Getting a Norplant: The 6-capsule Norplant re- diaphragm requires a fitting in a clinic. Lea’s Shield (Canadian brand; in US: leasing levonorgestrel was withdrawn During the fitting, a fitting ring is in- Lea Contraceptive, in Europe: LEA con- from the market in 2002. serted into the vagina. The largest ring traceptivum) is a female barrier method that fits comfortably is usually the one of contraception, reusable, made of Jadelle: Jadelle contains two flexible, chosen. Diagphragms can be inserted up medicalgrade silicone, inserted in the silicone-based polymer rods that are

J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) 29 Contraception – Update and Trends

sician skilled in this technique. The Table 1: Implantables implantation should be done at the Progestin Trade name Unit Duration of action inner part of the upper arm approxi- mately 8–10 cm above the medial Levonorgestrel* Norplant 6 capsules 5 years epicondylus of the humerus. In right Levonorgestrel Jedelle 2 rods 5 years hander patients the left arm should be Etonogestrel Implanon 1 rods 3 years Nestrone Elcometrine 1 capsule 6 months preferred. After the correct insertion ® Nestrone Elcometrine 1 rod 2 years Implanon can be immediately and Norgestrel Unilant or Surplant 1 rod 1 year during the complete period localized by palpation. If it is no palpable a lo- *) Norplant distribution in the United States ended in 2002 calization can be done with high frequence ultrasound using ultra- sound heads with high resolution or 43 mm in length and 2.5 mm in dia- Note: Incident data especially come computer tomography [80–82]. In meter; each rod contains 75 mg levonor- from observation of full three years of single cases a small operation with an gestrel, low levels of which are continu- use, whereas the typical observation pe- incision of up to 1 cm might be nec- ously released into the blood over riod for e. g. a new COC is one year in essary. Already one week after re- Jadelle’s period of use, approved by the the phase 3 studies. Incidence data moval of the implant, etonogestrel is U. S. Food and Drug Administration should thus be seen in perspective of this not detectable anymore in the serum (FDA) for up to 5 years. much longer observation period and not [68]. After the removal of Implanon® be seen as higher than COCs. ovulation as well as fertility occur Implanon: Implanon is a non-biode- fast [66, 67, 83]. gradable, longacting, progestagen-only The impact on bone density has been inserted subder- analysed in two clinical studies. In a Summary: The main benefit of any con- mally. The implant is a single rod of 2year trial enrolling a total of 73 healthy traceptive method is efficacy and the 4 cm length and 2 mm in diameter and women Beerthuizen could not find sig- CHMP considered that Implanon shows contains 68 mg etonogestrel (ENG) dis- nificant changes in bone density at the excellent efficacy with no evidence of persed in a matrix of ethylene vinyl ac- lumbal spine, the proximal femur as well decline neither during the 3rd year of use etate (EVA) copolymer. The indicated as distal radius between Implanon® users nor in heavy women. period of use is 3 years. The ENG dose and IUD users. It has been concluded released by Implanon is equivalent to that by maintenance of the endogenous In Germany there is a special official ® 6070 µg/day shortly after insertion and FSH and E2 levels in Implanon users recommendation to use Implanon only decreases to about 40 µg/day at the start occur no estrogen deficiency symptoms after intensive counselling of the patient of the second year, and to about 2530 µg/ and subsequent no bone loss [75]. In and information about the possible risk day at the end of the 3rd year. contrast, Bahamondes found in a study associated with Implanon® removal [84]. enclosing 111 women, conducting a – Contraceptive Efficacy: Pearl-Index: bone density measurement before and 18 (Author’s comment: Traning in insertion 0,04–0,08. The contraceptive effi- months after insertion of a etonogestrel and removal is essential. If you are expe- cacy is mainly based on ovulation in- or a levonorgestrel containing implant, a rienced in Implanon insertion and do it hibition [66, 67]. Within 8 hours af- slight but significant change at the correct subdermally, you will have no ter subdermal implantation the serum middle part of the ulna whereas the distal problem with removal) (see also [85]). levels of etonogestrel reach values radius remainded unchanged [76]. sufficient for ovulation inhibition In total, about 5 million Implanon im- [67, 68]. An additional contraceptive In summary, the CHMP agreed that there plants have been sold worldwide up to effect is based on increased viscosity is at this time no firm evidence of an as- July 2008. of the cervical mucus [66]. sociation between Implanon exposure and an increased risk of breast cancer in Implanon NXT: A new radiopaque Drug interactions can occur in view to young women. Implanon NXT (2× 40 mm), which can an induction of microsomal enzymes, es- be easily located, using xray, will be pecially cytochrom-P 450-isoenzyme – Breast Feeding Women: Implanon® available worldwide 2010 by MSD. The which leads to a increased metabolism of seems to have no impact on the qual- core of the implant consists of 37 % eth- steroid hormones [69, 70]. ity and quantitiy of the milk of ylene vinyl acetate as copolymer, 60 % breastfeeding women and no impact etonogestrel (68 mg) and 3 % barium – Side effects: Type and incidence of on the development of the child [77– sulfate. In addition the inserter has been side effects are similar to other 79]. It can be used during the breast improved leading to an insertion of the progestin only contraceptives. The feeding period. The growth and de- implant in the subdermal tissue not most important side effects are velopment of the child should be deeper than 4 mm (Fig. 7). bleeding disorders, vaginitis, acne carefully observed. vulgaris, breast pain, head ache, – Insertion and Removal: The implan- In a Cochrane analysis Power et al. [86] weight increase, mood changes and tation and removal of Implanon® found, that all the trials identified com- abdominal pain [71–74]. should be exclusively done by a phy- pared different types of contraceptive

30 J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) Contraception – Update and Trends

these methods, except that women on DMPA are more likely to experience cessation of vaginal bleeding during its use. There was inadequate data to detect differences in some non-menstrual clini- cal effects, and considering that this con- traceptive method remains in use in some countries, further research is indicated.

DeposubQ provera 104™: A new three-month injectable (Sayana) con- taining low dose depot medroxyproges- Figure 7: Implanon NXT (due to the content of barium sulfate it can be easily located by x-ray). Reprint with permis- terone acetate (104 mg) has been re- sion from MSD. cently introduced by Pfizer. DeposubQ implant. No trials were found that com- in an oily liquid which provides effective provera 104™ (deposubQ) is a new for- pared implants to other contraceptive contraception for 2 months. Further- mulation of the injectable contraceptive methods. All the implants were highly more, there is a high incidence of amen- DepoProvera®. Administered through effective methods of contraception in the orrhoea (50 % after one and 75 % after subcutaneous injection, deposubQ con- selected women. The majority of women two years). Migraine and headache are tains 30 % less depot medroxyprogeste- using contraceptive implants chose to also common. rone acetate (DMPA) than the intramus- continue with the method long term, cular presentation (DMPA IM, 150 mg/ml over 80 % of women were still using With regard to bone metabolism: medoxyprogesterone acetate sterile aque- their implant at two years. Women in – There should be no restriction on the ous suspension) while providing equiva- developed country studies were less use of DMPA, including no restric- lent efficacy and safety. DeposubQ is likely to continue with these methods tion on duration of use, among indicated for the prevention of preg- when compared to women in developing women aged 18–45 years who are nancy in women of childbearing poten- country studies. The most common re- otherwise eligible to use the method. tial and for management of endometrio- ported side effect was of irregular vagi- – Among adolescents (menarche to sis-associated pain (Author’s comment: nal bleeding. Bleeding with all implants < 18) and women over 45 years, the not yet in Germany). became less frequent with time. Re- advantages of using DMPA gener- moval was quicker for Implanon and ally outweigh the theoretical safety DeposubQ provera 104 mg/0.65 ml con- Jadelle than for Norplant. Insertion concerns regarding fracture risk. tains medroxyprogesterone acetate problems were rare with any of the im- Since data are insufficient to deter- (MPA), a derivative of progesterone, as plants. Problems at removal were un- mine if this is the case with long-term its active ingredient. When deposubQ is common but were significantly more use among these age groups, the administered to women every 3 months likely to occur in Norplant users than overall risks and benefits for con- (12–14 weeks), it inhibits the secretion Implanon users. Comment: This analysis tinuing use of the method should be of gonadotropins, preventing follicular needs to be updated. reconsidered over time with the indi- maturation and ovulation and causing vidual user. endometrial thinning. Because DMPA is Trends – Recommendations regarding DMPA absorbed more slowly when adminis- The following contraceptive implants use also pertain to use of NETEN. tered subcutaneously, a 30 % lower are in development: Elcometrine con- – There should be no restriction on the dose of deposubQ in comparison with sists of 1 capsule with nestrone acting use of other progestogen-only con- DMPA IM allows for a lower peak MPA over 6 months; Elcometrine using 1 rod traceptive methods among women concentration and aboveminimum se- with nestrone and an efficacy over who are otherwise eligible to use rum MPA levels for suppressed ovula- 2 years and Uniplant or Surplant with these methods, including no restric- tion over a targeted 3 months [89]. 1 rod containing norgestrel over 1 year. tions on duration of use. New biodegradable implants (capsules – There should be no restriction on the – Effectiveness: As the following or rods) and implants with new steroids use of combined hormonal contra- clinical evidence suggests, deposubQ have been under investigation for years. ceptive methods among women who provides equivalent efficacy, safety, are otherwise eligible to use these and immediacy of onset to that of Depot Injectables methods, including no restrictions DMPA IM and effectively suppresses Update on duration of use [87]. ovulation for at least 13 weeks re- In 1992, the FDA approved depot me- gardless of race, ethnicity, or body droxyprogesterone acetate (DMPA) as a In a Cochrane analysis, Draper et al. [88] mass index (clinical studies have long-acting, injectable progestational compared depot medroxyprogesterone been performed between body mass contraceptive. DepoProvera is medroxy- versus for index 18.2 and 46.0 kg/m2). progesterone acetate aqueous suspen- long-acting progestogenic contracep- – Pearl-Index: In 2 Phase-III-Studies sion 150 mg in 1 ml which must be ad- tion. In summary, therefore, data from with a total of 2045 users (18–49 ministered every 3 months. Noristerat is the trials included in this review indicate years, at least 20,000 cycles) after norethisterone enantate 200 mg in 1 ml little difference between the effects of one year no case of unintended preg-

J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) 31 Contraception – Update and Trends

nancy occurred. This corresponds to • Improved pharmacokinetic profile Today, based meth- a pearl-index of 0. – Biodegradable microspheres: nor- ods are a good choice for women or – Pharmacokinetic: After subcutane- , norgestimate, pro- couples seeking a safe and healthy ous injection of 104 mg MPA within gesterone method at low cost. Disadvantages in- 24 hours the contraceptive serum – Controlled particle size distribu- clude the necessity of a learning phase level of MPA (> 0.2 ng/ml) is tion: depot medroxy progestero- and the challenge of sexual behaviour. achieved which remains at least for neacetate (DMPA), levonorges- 13 weeks. trel butanoate Besides contraception, NFP can also be – Contraindications and side effects: • Decreased side effects integrated into the management of sub- DeposubQ is expected to have – Monolithic macrocrystals: pro- fertility and is an interesting contribu- equivalent, if not improved, toler- gesterone, 17-beta-estradiol, test- tion to gynaecological endocrinology: ability in comparison with the osterone combined for once-a- long-term cycle monitoring may support DMPA IM formulation because side month administration medical diagnosis and therapy. For all effects are generally dose-dependent • Safer delivery system applications, effective use depends on [90]. Contraindications are identical • Provision of cyclofem in non-reusable good instruction of the women. to those of DMPA IM, and common disposable syringes (Uniject, Soloshot). side effects for both deposubQ and Cycle monitors promise to detect the fer- DMPA IM include headache; bleed- Natural Family Planning tile and infertile days by using different ing irregularities (including amenor- Update markers of fertility in a woman’s men- rhea, irregular spotting or bleeding, Recently, interest in natural family plan- strual cycle. Actually, there are different prolonged spotting or bleeding, and ning methods has seen a modest resur- computer thermometers (e. g. Cyclotest®, heavy bleeding irregular bleeding gence. Based on fertility awareness, Babycomp®, Bioself®) and hormonal gad- typically decreases over time, and women are able to identify the fertile gets (e. g. Persona®, Ovarian Monitor®) amenorrhea becomes more common); window as well as peak fertility in their available. They are quite interesting, but increased weight; and injection site cycle without much effort. NFP meth- are less effective than the STM (medium reactions typically mild injectionsite ods include avoiding sexual intercourse efficacy) [96]. pain, granuloma or atrophy. While (or use a barrier contraceptive, like a use of DMPA IM and deposubQ is ) on the fertile days. The Symp- Trends associated with decreased bone min- tothermal Method (STM) combines the Fancy monitoring devices for follicular eral density, no evidence suggests observation of the periovulatory tem- maturation and ovulation failed to show that use of DMPA leads to signifi- perature rise and cervical mucus changes a benefit for contraception and most of cantly increased risk of bone fracture and determines the onset as well as the them have been offered for cycle moni- [91]. Bone loss associated with end of the fertile phase according to the toring in infertile patients. DMPA use is reversible, and prior doublecheck principle. use of DMPA is not likely to be an Spermicides important risk factor for low bone Grimes et al. [93] published a Cochrane Update density or fracture in older women analysis on the randomized controlled Spermicides are chemical products in- many years after discontinuation trials that compared NFPmethods. Two serted in a woman’s vagina before sex [92]. trials were found, one from Colombia that inactivate or kill sperm. They have and one from Los Angeles, California. been available for more than 40 years, Trends Both revealed poor research methods and the rigorous contraceptive testing See also once-a-month injectable. and must be regarded as having failed. In required today by the U.S. Food and contrast, certain (mainly European) Drug Administration was not required at Several progestin-only injectables are in variations of the symptothermal method the time of their approval. The main use or under investigation in various have turned out to be highly effective: chemicals used in spermicides are non- countries. Injectables using microsphe- Actual data on prospective observational oxynol-9, octoxynol-9, menfegol, and res or microcapsules containing one or studies found a method-effectiveness of benzalkonium chloride. Of these, non- more hormones also are under investiga- 0.4 pregnancies per 100 women years, oxynol-9 is the most common. Research tion. A sterile solution suspends the provided the appropriate guidelines are on the effectiveness of spermicides, par- time-released spheres. The microsphere consistently adhered to [94, 95]. There- ticularly nonoxynol-9 (N-9), to reduce contains a polymer commonly used in a fore, these methods belong to the most transmission of sexually transmitted dis- biodegradable suture, polydllactideco- effective methods of family planning and eases has provided conflicting results. A glycolide. Depending upon the formula- may also be an option for patients at risk. recent statement from the Medical Advi- tion, injectable microspheres provide sory Panel of the International Planned contraception for 1, 3 or 6 months. Men- There are two new methods which are Parenthood Federation recommends that strual disturbances are the primary side less effective and actually recommended N-9 should be used only in combination effect. for developing countries: The standard with a female mechanical barrier method day method is based on abstinence/pro- and that condoms prelubricated with N-9 Further improvements as mentioned tection from cycle days 8 to19. The “two have no advantage in contraceptive effi- by the WHO (according to [1] are day” method is based on cervical mucus cacy and should no longer be recom- based on: observation. mended.

32 J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) Contraception – Update and Trends

Spermicides can be bought over the still around five years away from being ring at the closed end to aid with inser- counter from the chemist or pharmacist. tested in humans. tion, and a larger flexible ring that re- They are available as creams or gels. The mains outside the vagina at the open end active ingredients include nonoxynol-9 • Internet Links to help protect the external genitalia. and octoxinol. – Microbicides: STD protection Since its introduction in the early 1990s, with or without contraception the has become an im- Trends (http://www.csa.com/discovery portant option to assist some women in Spermicides with antimicrobiotic activ- guides/micro/overview.php?SID= protecting themselves and their partners ity are under way to provide additional 9jlmaiv73hts256smm41b5uou2) from unwanted pregnancies and sexually protection against HIV and other sexu- – Contraceptive methods: Spermi- transmitted infections. The only cur- ally transmitted diseases. cides (http://www.rho.org/html/ rently available female condom is the contspermicides.html) soft, transparent, polyurethane sheath in- Microbicides with contraceptive ac- serted in the vagina before sex. Although tion (according to [1]: Vaginal sponges the device is marketed and approved as a – Products that create a protective physi- Update single-use-only device, reuse by women cal barrier in the vagina: e. g. sulfated Natural sea sponges soaked in spermi- who are not able to access a new female and sulfonated polymers, such as cel- cide and inserted in the vagina before in- condom has been reported in a number lulose sulfate, polystyrene sulfonate. tercourse have been used throughout his- of countries. The female condom is four – Products which increase vaginal de- tory for contraception. In the past de- times more expensive than male fense mechanisms by maintaining cade, several companies have worked to condoms. natural acidity (which immobilises update and reintroduce this method. The sperm): e. g. BufferGel and Acidform. sponge creates a physical barrier be- New female condoms under way accord- – Surfactant products: e. g. acylcarni- tween the semen and the cervix and traps ing to the WHO [1] are: polyurethane fe- tine analogs, C31G. the sperm in the sponge. It also acts as a male condoms (PATH), female condoms – Products which block attachment of chemical barrier by releasing spermi- made of natural latex (Reddy, other) or HIV to target cells and spermzona cide. Three contraceptive sponges are plastic material. pellucida fusion: e. g. naphthyl urea currently available in some countries. derivatives. The sponge provides between 12 and 24 Femidom (made of polyurethrane) is hours of protection, depending on the avaiblabe since several years. FC2 Algae gel against HIV: New gel de- brand used. (made of nitrile), V-Amour (made of la- rived from algae are in clinical trials in tex) are the names of the new products view to a possible HIV protection. In Protectaid: The new Protectaid® contra- on the market. preliminary lab tests they say it proved ceptive sponge is a unique barrier con- to be 95 % efficient. The inventor hopes traceptive device made of polyurethane Female Sterilisation the gel – one of a new generation of foam impregnated with F5 Gel®. The in- Update microbicides seen as key to prevent HIV dividually wrapped sponge is ready to Sterilisation (female and male) is still infection in women – will be on the mar- use and is designed with diecut slots for the most widely used method of fertility ket in 7 years (http://news.bbc.co.uk /2/ easy insertion and removal. regulation in the world. It is estimated hi/health/6266527.stm). that 187 million couples rely on female The Today Sponge is a small polyure- sterilisation worldwide, and a further 42 Cellulose sulfate gel against HIV: A thane foam sponge containing 1 g of million rely on male sterilisation (WHO WHO trial in South Africa and India nonoxynol-9 (N-9). It is a one-size, over- Research on Reproductive Health 2000– testing an anti HIV gel containing cellu- the-counter product and can be worn for 2001). The highest prevalence of female lose sulfate has been recently stopped. 24 hours. It was approved by the FDA in sterilisation in the world is in Puerto 1983 for sale in the United States. In Rico (49 % of women of reproductive „Molecular condom“: ‘Smart’ vaginal 1994, the manufacturer halted produc- age who were ever in a union are steril- drug delivery system (DDS), called a tion of the device because of production ized) [97]. ‘molecular condom’. It is composed of a problems. The product line was bought biologically responsive polymer that is a by Allendale Pharmaceuticals in 1995, For many women in developing coun- liquid at room temperature (for im- who has been trying to reintroduce pro- tries, sterilisation is the first-choice proved coating of tissue) and gels when duction for the U.S. market. In June method of contraception that they use. it comes in contact with tissue at body 2005 the Today Sponge returned to Tubal sterilisation is the most common temperature (for improved retention). stores in the United States. The Today method of contraception used in the The gel system is pH sensitive so that Sponge is also available in Canada. United States. More than 10 million when the molecular condom comes in women in the United States are steril- contact with semen it liquefies and re- Female Condom ised. The Centers for Disease Control leases entrapped antivirals into semen in Update and Prevention reported cumulative a burst profile (http://www.bioen.utah. The female condom is a sheath made of pregnancy rates for surgical sterilisation edu/faculty/pfk/pages/projects_3.htm)“. thin, transparent, soft plastic that a in the United States of 5.5 pregnancies/ However, the technology, featured in the woman inserts in her vagina before sex. 1000 women at 1 year, 13/1000 at 5 years, Journal of Pharmaceutical Sciences, is It has two rings: a flexible removable and 18.5/1000 at 10 years. That is, there

J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) 33 Contraception – Update and Trends

Figure 8: New female sterilisation techniques. From JRE 2007; 4(6): 337– 57. Left: Upper figure: ; reprint with permission from Conceptus Inc. Lower figure: Adiana. Source: www. thewelltimedperiod.blogspot.com; reprint with permission. Right: Ovabloc. Source: www.ovabloc.com/ovabloc-de/ eingriff.html; reprint with permission from aap bio implants group. were almost two pregnancies per 100 than mini-laparotomy, but it requires rate of the levonorgestrel IUS (Mirena) women by 10 years, though this risk var- more sophisticated expensive equipment which offers additional non-contracep- ied by method and timing of steriliza- and greater skills. Culdoscopy has tive benefits whilst providing the same tion, age, race, and ethnicity [85]. higher rates of complications. efficacy in contraceptive reliability.

Tubal ligation or sterilisation (tying the Quinacrine: Since more than 20 years a • Internet Links: tubes) is a common method of fertility chemical sterilisation with Quinacrine is – Bulletin of the World Health regulation. It is usually done by using the evaluated in clinical triats: Occlusion of Organization. Bull World Health following methods: mini-laparotomy the fallopian tube by introduction of the Organ 81(2) Geneva 2003 (through a small cut in the abdomen), polymerising agent Quinacrine. (http://www.scielosp.org/scielo. php laparoscopy (“keyhole” surgery through ?pid=S004296862003000200013& a tube inserted through the umbilicus New techniques for female script=sci_arttext) (belly button) or a very small cut), or cul- are: – Reproductivehealth/Unintended doscopy (using a tube, but through the Pregnancy/Sterilization (http:// vagina) [98]. Essure: Hysteroscopic sterilisation by www.cdc.gov/reproductivehealth/ insertion of titanium in the proximal part UnintendedPregnancy/Steriliza- In a Cochrane analysis, Nardin et al. [98] of the fallopian tube (Fig. 8). Essure is tion.htm) analysed the techniques for the interrup- not available in family planning pro- tion of tubal patency for female sterilisa- grams in developing countries, nor is it Immunocontraception tion. Effective techniques for tubal likely to become available, because of Update sterilisation (blocking the fallopian considerations of cost, practicality, and Immunocontraception is a non-hor- tubes) include cutting, tying, clips, rings (the lack of) comparative advantage monal, nonsteroidal method of contra- and electric current, but their compara- [85]. ception. Various targets have been dis- tive effectiveness is not clear. The re- cussed. Oocyte antigens, sperm anti- view of trials found that all techniques Adiana: Heating the inner lining of the gens, immunisation against GnRH etc. are effective in preventing pregnancy, fallopian tube by radiofrequency and in- with few adverse effects. There is too sertion of a soft, inert polymer matrix via Oocyte antigens: One target for immu- little evidence to which technique is a delivery catheter (Fig. 8). nocontraception are the surface antigens most effective. Pregnancy after tubal (ZP1, ZP2, ZP3) of the oocyte which sterilisation is less likely if an experi- Ovabloc: Sterilisation method for play a role in sperm attachment and pen- enced practitioner has performed the women whereby a rubber plug is in- etration, based on the use of porcine procedure. serted into both fallopian tubes (Fig. 8). zona pellucida (pZP) proteins. In ani- mals, pZP vaccine creates an immuno- In another Cochrane analysis, Kulier et Trends logical response. An antibody layer forms al. [99] analysed mini-laparotomy and Improvement of endoscopic techniques around the egg cell which binds to and endoscopic techniques for tubal steril- for surgical sterilisation. Decreasing blocks the sperm receptor sites, thus pre- isation. The review found that overall, number of female sterilisations in devel- venting penetration of the sperm cell and laparoscopy had fewer complications oped countries due to a high acceptance successful fertilisation. Blocking of all

34 J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) Contraception – Update and Trends sperm receptor sites relies on antibody • Continuous regimen: • Internet Links concentrations that are sufficiently high – Mifepristone 0.1–10 mg/day – Population Reports (2005): to achieve this and should the concentra- • Weekly use: Novel, GeneBased Approaches tions fall below a critical level, which – Mifepristone 2.5–50 mg doses Promise Dramatic Change in Con- happens over time, the cow will once • Monthly use: traception (http://www.infofor again be fertile. pZP only targets the – Mifepristone 200 mg 2 days after health.org/pr/m19/supplements/ zona pellucida of the female animal and the LH peak novel.shtml) has no direct effect on behaviour. Be- • Emergency contraception: cause the animal does not fall pregnant – Mifepristone 10 mg Anti-Implantation Agents she will continue to show an oestrous. Anti-implantation agents are intended to The use of progesterone receptor modu- be taken on only one occasion during the Spermatocyte antigens: Fertilisation- lators for postcoital contraception based menstrual cycle. They could be used related antigens at the surface of sperma- on inhibition of follicular growth and regularly as a once-a-month method or tozoa are also a target for immuno- ovulation inhibition has been discussed less frequently on an “as-needed” basis contraception. While there are several in the chapter on emergency contracep- in the absence of regular contraception, lines of evidence pointing to the possi- tion. or as a back-up method in the event of bility of inducing immunity to sperm, in suspected failure of a regular contracep- practice many roadblocks have appeared Implantation Inhibition tive method. They could be free of the such as sperm antigens that cross-react Immunocontraception logistical problems associated with the with other somatic antigens, effective Immunocontraception is focussing on provision and use of some other family sperm antigens that do not affect fertil- inhibition of implantation of the early planning methods, they could also have ity, short-acting immunity, and the prob- embryo development. The method fewer side effects, and their infrequent lems of producing high titers in the local developed by WHO is based on, and use would make them relatively inex- environment of the genital tract. The directed against, human chorionic gona- pensive. female genital tract is not rich in lymph dotropin (hCG), a hormone produced by tissue but IgG and IgA antibodies do the early embryo within a few days after A collaborative initiative on basic re- occur there, probably originating from fertilization and which is necessary for search in implantation between the gut-associated lymphoid tissue. Not only the maintenance of pregnancy. As the Rockefeller Foundation and HRP was is a very high titer of antibodies needed result of a large number of studies com- established in 1998 to help in the devel- to block fertilization in vivo but local paring a variety of preparations, a novel, opment of such a method, which is still immunization is ineffective in inducing slow-release formulation of the hCG at an early stage. high titers. Probably combined local immunocontraceptive has been selected and systemic routes will be required. for clinical evaluation. This preparation Several sperm antigens such as lactate offers the promise of providing 6 months „ Summary dehydrogenase C4, PH-20, sperm pro- or more of protection against pregnancy The variety of contraceptive methods tein (SP)-10, fertilization antigen (FA)-1, following a single injection, without available today spans a broad spectrum, FA-2, cleavage signal (CS)-1, NZ-1, and producing side effects that would make and to help facilitate the selection pro- NZ-2 have been proposed as potential it unacceptable for use. The preparation cess. Physicians need to be aware of the candidates for vaccine development has been evaluated for safety and characteristics of each option. An in- [100]. potency in preclinical studies in animals formed physician can help patients make and an application has been made to the best choice for their particular medi- Trends the drug-regulatory authorities to carry cal, social, and philosophical require- The possible hazards of immunocontra- out a dose-ranging, Phase-I clinical trial ments or preferences. ception are cross-reactions of the anti- with this preparation in women volun- body of non-reproductive tissue, unpre- teers. However, existing methods of contra- dictable titers of antibody leading to a ception are not perfect, and their accept- prolonged sterilisation, and other safety Also promising are the female genes and ability is limited by side effects and in- issues. Immunocontraception is gaining proteins responsible for sperm-egg fu- convenience. Even in developed coun- more and more importance in animal sion: tries where contraception is freely avail- contraception (e. g. rabbits, deer etc.). able, many unplanned pregnancies oc- Zygote arrest 1 (ZAR1) gene plays a cur. There is thus a real need for new Antiprogestins central role in the fusion of the sperm methods of contraception to be devel- Antiprogestins for contraception can be and egg pronuclei, the nuclei containing oped that are more effective, easier to used according to the WHO in different genetic matter. use, and safer than existing methods. regimens [1]: • Sequential regimens: Bin1b binds to the heads of sperm, Predicted Developments (modified ac- – Mifepristone + Norethisterone inducing sperm motility. Blocking the cording to [1, 101]): – Mifepristone + Medroxyproges- action of this molecule could have a terone acetate contraceptive effect because sperm Within 5 years: New delivery systems – Mifepristone (days 1–15) + No- would not be able to reach or penetrate of conventional contraceptives such as megestrol acetate (days 16–28) the egg. vaginal rings, transdermal patches, and

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