Ariel B. Handy & Cindy M. Meston

Conception and Contraception

Pregnancy occurs when a sperm fertilizes an egg, which then successfully implants in the uterine lining. Prior to ovulation, estrogen levels peak, which causes the pituitary gland to release a surge of follicle stimulating hormone and luteinizing hormone (for a review, see Watson & Stacy, 2011). The rise in follicle stimulating hormone facilitates the maturing of eggs within the ovaries (as reviewed in Hillier, 1994). Once mature, a single egg from one ovary is released, and the body reabsorbs the remaining matured eggs. The release of luteinizing hormone triggers the thickening of the uterine lining in preparation for the implantation of a fertilized egg (Watson & Stacy, 2011).

The mature egg travels from the ovary through the fallopian tubes, where a sperm may fuse with and fertilize the egg. After fusion, the cells within the egg begin dividing and the egg continues traveling through the fallopian tubes towards the uterus, where it embeds within the uterine lining (see Marieb & Hoehn, 2016, for a review). The follicle that released the egg transforms into a corpus luteum, which is a cluster of sex steroid hormone-producing cells. The corpus luteum induces is a large surge in progesterone and a small increase in estrogen, which assists in the production of the uterine lining and protects against shedding (i.e., menstruation; Watson & Stacy, 2011). Specifically, the surge in progesterone initiates the transformation of the uterine lining from proliferative to secretory, reflecting increased thickness of the lining in preparation for egg implantation. If no egg implants within the walls, progesterone levels fall, the endometrium breaks down, and the menstrual cycle resumes (see Hobeika et al., 2020, for a discussion).

Whereas non-hormonal forms of contraception work by preventing sperm from reaching the egg (e.g., condoms) or by blocking the reproductive function (i.e., surgical sterilization), hormonal methods (e.g., some intrauterine devices, OCPs) operate by either preventing an egg from being released or preventing a fertilized egg from implanting in the uterus. Oral contraceptive pills contain synthetic hormones. There are two main classes of OCPs: combined OCPs, which contain synthetic estrogen and progestin, and progestin-only pills. The exogenous hormones provided by both combined OCPs and progestin-only pills are metabolized in the liver and, in response to this, the liver increases the production of the protein sex hormone binding globulin (SHBG; for a review, see Stuckey, 2008). As the name suggests, sex hormones bind to SHBG and are rendered inactive. Of estrogens, progesterone, and androgens, androgens have the highest affinity for SHBG and are thus most likely to bind to this globulin and become inactive (Rosner, 1991). Certain progestins (e.g., doestrogel) increase liver production of SHBG to a greater extent than others (e.g., levonorgestrel); the production of SHBG will increase or decrease based on the androgenic or antiandrogenic properties of the progestin (see Darney, 1995, for a review). The decrease in ovarian production of sex hormones and increase in production of SHBG can result in roughly a two-thirds reduction of bioavailable androgens (for a review, see Zimmerman, Eijkemans, Coelingh Bennink, Blankenstein, & Fauser, 2014).

Oral contraceptive pills inhibit the production of follicle stimulating hormone and luteinizing hormone within the pituitary gland (Rivera, Yacobson, & Grimes, 1999). Without the rise in follicle stimulating hormone levels, follicles do not facilitate the maturing and release of eggs from the ovaries, and ovulation is therefore suppressed (Frye, 2006). The consistently low levels of luteinizing hormone maintain a thin uterine lining that is inhospitable to the implantation of an egg if ovulation were to occur. It is for this reason that OCPs are often prescribed for the

management of menorrhagia, or heavy menstrual bleeding (Farquhar & Brown, 2009): a thinner uterine lining will lead to lighter menstrual bleeding.

The inhibition of follicle stimulating hormone and luteinizing hormone also significantly reduces the ovarian production of the sex steroid hormones estrogen, progesterone, and androgens. As the ovaries are the primary production source of these hormones in women (Hobeika et al., 2020), the bodies of women taking OCPs rely on the synthetic hormones within the pill. Many OCPs provide the body with hormones similar in concentration to that of a post-ovulatory state (i.e., high doses of progesterone coupled with low doses of estrogen; see Rivera et al., 1999), which further protects against pregnancy by leading the body to believe that ovulation recently occurred, and an egg should therefore not be released.

Combined Oral Contraceptive Pills

Combined oral contraceptive pills contain synthetic forms of the hormones estrogen and progestin. Almost all combined OCPs contain ethinylestradiol, a synthetic estrogen. The concentration of ethinylestradiol varies by brand (typically between 15-50 μg) but is most often around 35 μg per pill (van der Westhuizen & van der Merwe, 2011). The primary way in which combined OCPs differ from one another is through their progestin component. Typical combined OCPs contain progestins from four main families: derivatives of 19-nortestosterone (estranes and gonanes), derivatives of 17α-hydroxyprogesterone (pregnanes), derivatives of 19-norprogesterone (norpregnanes), and one derivative of spironolactone (Schindler et al., 2003). As combined OCPs all suppress the production of estrogen, luteinizing hormone and follicle stimulating hormone (Rivera et al., 1999), they are all considered anti-estrogenic and anti-gonadotropic. The extent to which they are antiandrogenic varies by family: derivatives of 19-nortestosterone tend to lack androgenic effects, derivatives of 19-norprogesterone have varying degrees of androgenic activity,

and 17α-hydroxyprogesterone derivatives and drospirenone, the sole derivative of spironolactone, may exert antiandrogenic (i.e., antagonistic) activity (Schindler et al., 2003).

Progestin-Only Pills

Progestin-only pills contain a progestin without estrogen. For that reason, progestin-only pills are particularly suited for women where the estrogen in combined OCPs is contraindicated (e.g., women over 35 who smoke cigarettes), for breastfeeding mothers, and for older women. Similar to combined OCPs, progestin-only pills also suppress the production of estrogen, luteinizing hormone and follicle stimulating hormone (Rivera et al., 1999), and are therefore also considered anti-estrogenic and anti-gonadotropic. Common progestin-only pills contain low doses of 19-nortestosterone derivatives gonanes (e.g., levonorgestrel and desogestrel) or estranes (e.g., norethindrone or ethynodiol diacetate). To minimize adverse androgenic effects (e.g., oily skin, weight gain), the progestin dose in progestin-only pills is typically lower than that found in combined OCPs (de Melo, 2010).

ORAL CONTRACEPTIVE PILLS AND SEXUAL FUNCTION

Given the importance of estrogens and androgens and potential inhibitory role of certain progestins in genital blood flow and subsequent lubrication, it is possible that combined OCPs containing antiandrogenic progestins (e.g., 17α-hydroxyprogesterone derivatives, drospirenone) may negatively impact female sexual arousal.

Combined Oral Contraceptive Pills and Sexual Function

Research examining the effects of combined OCP use on sexual function is mixed. Whereas some studies report improvements in sexual function (Çetin, Keskin, Verit, & Yücel, 2015), a recent review of the literature indicated that decreases in lubrication, increases in vestibular pain, and thinning of the labia minora and vaginal introitus are common among

combined OCP users (Burrows et al., 2012). Indeed, an internet-based cross-sectional study examining combined OCP use and women’s sexual function found that women taking combined OCPs reported greater levels of vaginal dryness and sexual pain as well as decreased lubrication, arousal, pleasure, and orgasm frequency compared to women using nonhormonal forms of contraception (Smith et al., 2014). The authors suggest that these findings may be related to decreases in bioavailable androgens and direct structural effects of combined OCPs on the vagina. Indeed, the type (Pazandeh et al., 2017) and dose (Strufaldi et al., 2010) of estrogen have been implicated in sexual health outcomes. In an extensive study involving 2,612 healthy medical students, similar findings were noted. Women taking combined OCPs scored significantly lower on the Female Sexual Function Index (FSFI; Rosen et al., 2000), the gold standard self-report measure of female sexual function, than did women using other forms of contraception (Wallwiener et al., 2015). However, the authors did not find any effect of estrogen dose or progestin type on self-reported sexual function, which suggests that changes in the number of bioavailable androgens may not have as large of an effect on sexual function as others have suggested (as reviewed in Bachmann et al., 2002). However, Wallwiener and colleagues (2015) proffered that any effects of estrogen dose or progestin type on sexual function may have been masked by confounding variables such as frequency of sexual activity. That is, if women had not recently (i.e., within the past four weeks, as is required for the FSFI) engaged in penetrative vaginal intercourse, their FSFI scores would have been lower than those of their counterparts. As this was not controlled for in the Wallwiener et al. study, effects of the OCP on FSFI scores could have been overshadowed by the effect of sexual inactivity on FSFI scores.

One limitation of the literature on combined OCP use and sexual function is the lack of randomized clinical trials. One recent study that attempted to address this limitation examined

changes in self-reported sexual function in 340 healthy women who were randomized to a common combined OCP (150 μg levonorgestrel and 30 μg ethinylestradiol) or placebo for 3 months (Zethraeus et al., 2016). Sexual function was measured via the Profile of Female Sexual Function (McHorney et al., 2004), a self-report scale assessing various domains of sexual function, at pre- and post-treatment. No differences emerged on overall sexual function; however, women in the combined OCP group scored significantly lower on the desire, arousal and pleasure domains compared to placebo at post-treatment. The authors speculated that there may be a “direct negative effect of the progestin component” of combined OCPs on sexual function (pp. 4050).

Progestin-Only Pills and Sexual Function

The effect of progestin-only pills on sexual function has received considerably less empirical attention than that of combined OCPs. However, a recent study examined self-reported sexual function (via the FSFI) among roughly 100 women using various forms of hormonal contraception (i.e., intrauterine devices, progestin injections, combined OCPs, and progestin-only pills) against 100 women who were not using hormonal contraception (Hassanin et al., 2018). Results indicated that FSFI desire, arousal, lubrication, and overall sexual function scores were significantly lower among contraceptive users compared to controls, and these results were maintained when comparing women taking any OCP (i.e., combined OCPs or the progestin-only pill) against controls. When the authors parsed apart the type of OCP women were using, they found that the FSFI desire, arousal, lubrication, orgasm, and overall sexual function scores were significantly lower in the progestin-only pill group compared to controls. Similarly, these domains were significantly lower in the progestin injection group compared to controls. The authors suggested that temporary contraceptive use can negatively affect sexual function, and this may be particularly true for progestin-based contraceptives. Similar reports have been described elsewhere in the literature (e.g., Pazandeh et al., 2017).