Winner essay of our Mind the Research Gap Student competition in partnership with WHAM, written by Ellen Wall, PhD student in Neuroendocrinology at the University of Cambridge.
"Ellen put the spotlight on the importance of laying strong research foundations to develop new drugs using contraception and the hypothalamic–pituitary–gonadal axis as example"
Introduction
Contraception refers to a method used to deliberately prevent a pregnancy following sexual intercourse. The various methods used differ in their efficacy, potential side effects and medical contraindications. They can be categorised based on their efficacy into; most effective (sterilisation, intrauterine device (IUD), intrauterine system (IUS), implant), effective (oral contraceptive pill, injection, transdermal patch), and less effective (condom, spermicides, rhythm method, withdrawal). Although the number of contraceptive methods available has increased considerably over the past few decades, still 45% of pregnancies in the UK are classed as either unplanned or ambivalent [1]. Furthermore, 84% of women reported using contraception between 1999-2000, however, a decade later this figure fell to 76% [2]. Additionally, within a year 5% of women stopped using their contraceptive methods and 12% switched methods leaving them vulnerable to an unplanned pregnancy. The main reasons reported for this switch were to seek an easier/more reliable option (48%) or due to side effects/health concerns (38%) [3]. This unmet need for adequate contraception highlights a major health and research gap in women’s healthcare.
The Gap
Healthcare
The role of the primary care physician is imperative in contraceptive care, as this is often the first point of contact. Long-acting reversible contraceptives (LARC) which include the IUD, IUS, implant, and injection are among the most effective forms of contraception [2]. In 2009, a pay for performance scheme for physicians to educate women on LARCs was introduced [4]. The aim of this incentive was not to coerce women into using LARCs but to empower them through education to make an informed decisions based on their current needs. This incentive resulted in a 13% increase in LARC uptake and a 38% reduction in the number of abortions reported. Although this proved highly successful, in 2014 the incentive ended. This led to an attenuation in LARC uptake within the adolescence age group, one which displays the highest proportion of unplanned pregnancy [1, 5].
Hormonal contraception, albeit one of the most common and effective methods, comes with a plethora of potential side effects ranging from mood and libido changes to nausea, headaches, and breast tenderness [6, 7]. In 2016, a phase II trial for a male hormonal contraceptive was terminated due to adverse side effects. In this study, 4.7% of males reported mood swings and 2.8% reported depression [8]. A year previous to this, an IUD was approved by the FDA which reported mood swings and depression in 6.3% and 8.3% of women, respectively [9]. This highlights the double standards that exist in women’s health and how women’s complaints have long been and continue to be trivialised when it comes to contraception [10].
Furthermore, hormonal contraceptives come with many contraindications which render them unsuitable and unsafe for some users. These include individuals with a history of breast cancer, smokers, those who suffer from migraine with aura or who are at an increased risk for developing venous thromboembolism [11]. Therefore, these women must seek non-hormonal alternatives, of which effective reversible methods are limited.
Research
Gender bias remains a pressing issue in preclinical basic research. Male animal models outnumber females by 5.5:1 [12]. This is in part due to female models being labelled as ‘too complex'.
Hormonal contraception exerts its effects locally by altering the lining of the uterus and cervical mucus and systemically by hijacking the hypothalamic-pituitary-gonadal (HPG) axis, thus preventing ovulation [13]. The hypothalamus is a structure within the brain that plays a major role in regulating reproductive hormones. It does this by releasing gonadotrophin-releasing hormone which acts on the pituitary to release luteinising hormone and follicle-stimulating hormone. These then act on the gonads, the ovaries in women, to result in the release of sex hormones oestrogen and progesterone. In a healthy menstruating woman, following the mid-cycle ovulation, progesterone levels dramatically increase and exert a negative feedback action onto the hypothalamus. However, the exact mechanism by which progesterone negatively feeds back to the hypothalamus remains unknown. How can we adapt this system to our advantage if we cannot decipher the mechanisms of action of hormones under normal physiological conditions?
Bridging the Gap
Funding
Contraception is a highly cost-effective public health strategy. It does this by reducing the number of unintended pregnancies, resulting in a £9 saving for every £1 invested [14]. Therefore, not only is contraception beneficial to the individuals involved but it is also in the best interest of society. This strengthens the argument for investments to be made in contraception, both at the level of healthcare and research.
Reducing side effects
As hormones interact with many systems, including more female models in basic research is crucial. This could help us better understand the aetiology of the side effects related to hormonal contraception whilst also increasing the validity of these models.
Many of the hormonal contraceptives on the market are prescribed on a trial-and-error basis and demonstrate a high inter-individual variability in their side effect profiles. Precision medicine has been emerging as an exciting promise for the future of contraception and is already being explored by FemTech companies. This could allow physicians to personalise contraception to individuals based on their genetics, lifestyle factors and environment.
Enhancing the research
In 2003, scientists discovered that the kisspeptin peptide and its receptor were vital for normal reproductive functioning [15, 16]. The kisspeptin neuronal population in the hypothalamus is now accepted as being the driving force of the HPG axis in rodents [17]. Thus, these neurons may serve as a target for novel contraceptives. This population of neurons are already being targeted for menopausal hot flushes [12].
Conclusions
The root of the issues surrounding contraception stems from a lack of research and funding for women’s health. Gender gaps in research continue to limit our knowledge in this field. The fundamental mechanisms underpinning the HPG axis are not fully elucidated. Therefore, many of the current contraceptive options today are built on unstable foundations. Increasing funding for basic research and healthcare would equip physicians with the right tools to meet their patient’s needs.
References
[1] Wellings K, Jones KG, Mercer CH, Tanton C, Clifton S, Datta J, et al. The prevalence of unplanned pregnancy and associated factors in Britain: findings from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). Lancet. 2013;382(9907):1807-16.
[2] French RS, Gibson L, Geary R, Glasier A, Wellings K. Changes in the prevalence and profile of users of contraception in Britain 2000-2010: evidence from two National Surveys of Sexual Attitudes and Lifestyles. BMJ Sex Reprod Health. 2020;46(3):200-9.
[3] Wellings K, Brima N, Sadler K, Copas AJ, McDaid L, Mercer CH, et al. Stopping and switching contraceptive methods: findings from Contessa, a prospective longitudinal study of women of reproductive age in England. Contraception. 2015;91(1):57-66.
[4] Ma R, Cecil E, Bottle A, French R, Saxena S. Impact of a pay-for-performance scheme for long-acting reversible contraceptive (LARC) advice on contraceptive uptake and abortion in British primary care: An interrupted time series study. PLoS Med. 2020;17(9):e1003333.
[5] Pasvol TJ, Macgregor EA, Rait G, Horsfall L. Time trends in contraceptive prescribing in UK primary care 2000-2018: a repeated cross-sectional study. BMJ Sex Reprod Health. 2021.
[6] L P. The combined oral contraceptive pill. InnovAiT. 2022;15(2):106-12.
[7] Buggio L, Barbara G, Facchin F, Ghezzi L, Dridi D, Vercellini P. The influence of hormonal contraception on depression and female sexuality: a narrative review of the literature. Gynecol Endocrinol. 2022;38(3):193-201.
[8] Behre HM, Zitzmann M, Anderson RA, Handelsman DJ, Lestari SW, McLachlan RI, et al. Efficacy and Safety of an Injectable Combination Hormonal Contraceptive for Men. J Clin Endocrinol Metab. 2016;101(12):4779-88.
[9] Liletta. LILETTA® safety and side effects for healthcare providers 2022 [Available from: https://www.lilettahcp.com/safety##. (Accessed April 15 2022)
[10] Stern J, Molin MS, Fernaeus M, Georgsson S, Carlsson T. Contraceptive counseling about adverse reactions of intrauterine contraception: Exploration of narratives found in web-based discussion boards. Midwifery. 2022;104:103166.
[11] Houvessou GM, Farias-Antunez S, da Silveira MF. Combined hormonal contraceptives use among women with contraindications according to the WHO criteria: A systematic review. Sex Reprod Healthc. 2021;27:100587.
[12] Karp NA, Reavey N. Sex bias in preclinical research and an exploration of how to change the status quo. Br J Pharmacol. 2019;176(21):4107-18.
[13] Teal S, Edelman A. Contraception Selection, Effectiveness, and Adverse Effects: A Review. JAMA. 2021;326(24):2507-18.
[14] Wikum J. Contraception: Economic Analysis Estimation of the Return on Investment (ROI) for publicly funded contraception in England: Public Health England; 2018 [Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/730292/contraception_return_on_investment_report.pdf. (Accessed April 15 2022)
[15] de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 2003;100(19):10972-6.
[15] Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS, Jr., Shagoury JK, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349(17):1614-27.
[17] Herbison AE. The Gonadotropin-Releasing Hormone Pulse Generator. Endocrinology. 2018;159(11):3723-36.