Human papillomavirus (HPV) infection is associated with genital warts, precancerous lesions, and cancers in both men and women. Many cervical, vaginal, vulvar, anal, and oropharyngeal cancers are attributable to HPV, with cervical cancer constituting 84% of all HPV-associated tumors.

 Although most HPV infections clear naturally or become dormant thanks to the immune system, a significant number of women will develop cervical dysplasia after HPV exposure, and a subset of these women will eventually progress to cervical cancer. It is estimated that by age 50, approximately 80% of all women will have had exposure to or been infected with 1 type of HPV; approximately 10% of these women will proceed to develop persistent HPV infection, which increases their risk of cervical cancer.

Studies have shown a causal relationship between HPV and cervical cancer, and high-risk HPV serotypes such as HPV-16 and HPV-18 are connected to 70% of cervical cancer cases.

 HPV vaccines were developed to prevent HPV-related diseases by stimulating the production of neutralizing antibodies that protect against type-specific HPV infection. Currently, commercially available HPV vaccines utilize virus-like particles (VLPs) of the L1 major capsid protein, the injection of which induces high titers of systemic antibodies that ultimately prevent the HPV virus from infecting the host cell.

There are 3 main types of HPV vaccines on the global market: 1) a bivalent vaccine, Cervarix (GSK), composed of HPV-16/18 VLPs and the proprietary adjuvant AS04; 2) a quadrivalent vaccine, Gardasil (Merck), containing HPV-6/11/16/18 VLPs, and an aluminum salt adjuvant; and 3) a 9-valent (nonavalent) vaccine, Gardasil 9 (Merck), based on the quadrivalent vaccine but containing VLPs of 5 additional oncogenic HPV serotypes: 31, 33, 45, 52, and 58. The 9-valent HPV vaccine was introduced with the goal of preventing 90% of cervical cancer cases globally. In 2016, the 9-valent vaccine was approved by the FDA with a 2-dose schedule in girls and boys aged 9 to
14 years, and it has since become the only HPV vaccine available in the United States 

Despite almost 2 decades of high-quality research demonstrating that HPV vaccines have excellent safety profiles, a worrisome trend has developed: Many patients or their parents cite concerns about vaccine safety as the reason for declining HPV vaccination. A recent cross-sectional study that investigated HPV vaccination trends in the United States noted that the percentage of caregivers for unvaccinated adolescents who cited vaccine safety as the primary reason to defer vaccination rose from 13% in 2015 to 23.4% in 2018.

 Exposure to vaccine misinformation, particularly through social media, could be a contributing factor to vaccine hesitancy. Therefore, it is of paramount importance that clinicians effectively address these safety concerns and dispel misinformation about HPV vaccines.

Since their licensure, more than 135 million doses of HPV vaccines have been distributed in the United States (with more than 270 million doses distributed worldwide).

 HPV vaccines are considered extremely safe. The most common adverse events (AEs) associated with HPV vaccines are minor and transient: local AEs (pain, itchiness, swelling, and redness at the injection site) and mild systemic symptoms (headache, nausea).

Rarely, patients experience dizziness and syncope, although syncope has been found to be more common in adolescents after receiving any vaccine.

 The incidence of severe allergic reaction (anaphylaxis) is exceedingly low (0.3-3 per million).

 Prelicensure clinical trials of HPV vaccines established their favorable safety profiles, and in recent years, more population-based studies have supported these findings. A Cochrane review in 2018 showed that although local AEs were more common in vaccinated subjects than in placebo recipients, there was no significant difference in mild and serious systemic AEs between vaccinated subjects and placebo recipients.

Additionally, since 2007, the Global Advisory Committee on Vaccine Safety (GACVS; established by the World Health Organization) periodically reviews new safety data on HPV vaccines. GACVS has found no significantly increased risk of the any of following conditions: Guillain-Barre syndrome, autoimmune conditions, or venous thromboembolic AEs.

 Additionally, GACVS has found no causal association between HPV vaccine and conditions including complex regional pain syndrome and postural orthostatic tachycardia syndrome. Although HPV vaccination is not recommended during pregnancy per the American Academy of Obstetricians and Gynecologists (ACOG), routine pregnancy testing is not recommended prior to vaccination.

 According to research findings, inadvertent exposure to HPV vaccine during pregnancy was not associated with increased rates of spontaneous abortion or adverse birth outcomes.

 HPV vaccine is safe and recommended for breastfeeding women who have not been previously vaccinated.

More recent population-based studies focusing on the 9-valent HPV vaccine continue to demonstrate its excellent safety profile, which is similar to that reported in prelicensure trials and in trials with the quadrivalent HPV vaccine.

Many claims surrounding the HPV vaccine are not based in evidence and should be refuted accordingly. A concern sometimes voiced by parents is that their adolescent children are “not sexually active” and that receiving the HPV vaccine would promote unsafe sexual behaviors among adolescents.

However, research has shown no significant association between legislation to increase HPV vaccination and changes in adolescent sexual behavior.

 Additionally, HPV vaccination was not associated with increased rates of sexually transmitted infection in a large population of female subjects.

 These data provide evidence that the claims that HPV vaccination encourages unsafe sexual activity are unfounded. Another concern has been raised regarding whether the HPV vaccine causes decreased fertility. Two studies have found no evidence that the vaccine is associated with either primary ovarian insufficiency or increased infertility.

Natural infection with HPV triggers an immune response both by formation of neutralizing antibodies and by cell-mediated immunity via cytotoxic T lymphocytes; however, this response is slow and titers of antibodies from natural infection are much lower compared with those seen after HPV vaccination.

 Currently, immunogenicity is determined by evaluating seropositivity, geometric mean titer, and antibody stability. In a study of young women who received the 9-valent HPV vaccine (NCT00543543), seropositivity to HPV-16/18 approached 100%, and most participants
(77.5%-100%) remained seropositive after 60 months.

 Variations in antibody titers have been observed according to age, sex, vaccine type, and vaccine dosage, and multiple studies have suggested that vaccine-induced antibody titers are significantly higher in younger recipients.

 It is important to note that the relationship between immunogenicity from HPV vaccine and the vaccine’s efficacy is not clearly characterized. For all HPV vaccines, no minimum level of antibody titer has been established as a threshold for efficacy.

Regardless of vaccine type or population, HPV vaccination has been shown to generate a durable, long-term immunogenic response, with studies showing stable antibody levels even 10 years after the initial vaccination.

 Results of a recent study in women in Costa Rica (NCT00128661) showed that a single dose of HPV vaccine achieved near 100% seropositivity and generated antibody titers that were 9-fold higher than those provoked by natural infection and that persisted for more than 7 years.

 It is worth noting that a single dose of vaccine produces antibody titers lower than those produced by 2 or 3 doses, thus precluding noninferiority studies. Large studies with long follow-up times are needed to evaluate the true efficacy of single-dose vaccination regimens.

The efficacy of 2-, 4-, and 9-valent HPV vaccines against oncogenic HPV infection has been extensively evaluated through clinical trials. The most critical measure of HPV vaccine efficacy is prevention of invasive cancer. However, cervical cancer develops over many years after initial HPV infection and is often preceded by persistent cervical dysplasia, which is detected via routine screening. Therefore, prevention of invasive cancer was replaced by surrogate end points in HPV vaccine efficacy studies. These end points included 6-month persistent vaccine type–specific HPV infection, cervical intraepithelial neoplasia grade 2 or higher (CIN 2+), cervical adenocarcinoma in situ (AIS), and anogenital warts. All 3 vaccines demonstrated similarly high efficacy (summarized in 

The initial clinical trials were conducted in women 16 to 26 years old using a 3-dose vaccination schedule. Later studies also included adult women 26 to 45 years old, adolescents using the 2-dose schedule, and women who received only a single dose of vaccine. Analysis was performed in women without previous HPV infection (HPV-naïve population) and in the overall population (regardless of prior HPV infection status). Across HPV vaccine types, higher efficacy was observed in the HPV-naïve population.

For the quadrivalent vaccine, the overall efficacy against persistent HPV-6/11/16/18 infection was 87% in the HPV-naïve group. In the same group, efficacy against external genital lesions as well as CIN 2+ associated with vaccine-type HPV was greater than 98%.8,36,37 For women 24 to 45 years old, vaccination efficacy against persistent type-specific HPV infection, CIN 1+, and external genital lesions was still above 89% in the HPV-naïve group, and efficacy in the overall population was 67%.

 It is worth noting that cross-protection against other HPV serotypes has been observed for both bi- and quadrivalent vaccines. This is not surprising, given that the additional oncogenic HPV serotypes are genetically related to HPV-16/18. The bivalent vaccine has been shown to provide higher efficacy against HPV-31, -33, and -45 through cross-protection compared with the quadrivalent vaccine.38,39 The 9-valent vaccine has the added benefit of providing coverage against additional oncogenic HPV serotypes. The efficacy of the 9-valent vaccine in preventing persistent infection with the 5 additional oncogenic HPV serotypes was 95% in both HPV-naïve women and the overall population. Efficacy against high-grade disease was 97% in HPV-naïve women and 81% in the overall population.

Early clinical trials also demonstrated high vaccine efficacy even in women who failed to complete the full vaccination series and received only 1 to 2 doses of vaccine. This finding led to trials that evaluated the noninferiority of a 2-dose vaccination schedule in young adolescents (9 to 14 years old). In a surprising finding, mean antibody titers were significantly higher in adolescents who received 2 doses of vaccine than in women aged 16 to 26 years who received 3 doses.

 In women older than 26 years, all 3 vaccines continue to demonstrate efficacy against persistent HPV infection and precancerous lesions, although efficacy is more pronounced in HPV-naïve women.

 Given that vaccine efficacy is highest in young women who are HPV naïve, the current recommendation is to start vaccination for all individuals at ages 11 to 12 years (and as early as 9 years) with a 2-dose schedule. Individuals older than 15 years would benefit from a 3-dose regimen.

More than 15 years has passed since the introduction of the first HPV vaccine, and studies focusing on the real-world effectiveness of the vaccine and possible herd protection have been conducted. These studies examine the long-term impact of HPV vaccines, especially at the population level. Early data show that HPV vaccines are effective in preventing HPV infection, precancerous cervical lesions, genital warts, and cervical cancer in the community. Importantly, these studies show a reduction in HPV prevalence not only in the vaccinated population but also in the unvaccinated population. A recent US study reported that in the 11 years after the introduction of HPV vaccines, detection of quadrivalent vaccine–type HPV in vaccinated women was reduced by approximately 80%, from 35% to 6.7%. Additionally, a decrease in the prevalence of 9-valent vaccine–type HPV was also observed in vaccinated women. Moreover, among unvaccinated women, the prevalence of quadrivalent vaccine–type HPV was also reduced by 40%, suggestive of
herd protection.

Along with the decline in HPV-6/11 infections, a decrease in the prevalence and incidence of genital warts has been observed. A Danish study found that the overall incidence of genital warts, which had been increasing in the country until 2007, started to decline shortly after initiation of HPV vaccination, with the most significant decrease observed in young women with high HPV vaccination rates.

Additional studies have investigated the association between HPV vaccination and the incidence of HPV-attributable cancers. A retrospective, population-based, cross-sectional study showed that after vaccine approval, the rate of decrease in annual cervical cancer incidence in 20- to 24-year-olds grew to 9.5% compared with 2.3% prior to vaccine initiation. This finding suggests that the accelerated decrease in cervical cancer incidence in younger women may be related to HPV vaccination.

 Another Swedish study that examined the relationship between HPV vaccination and risk of invasive cervical cancer demonstrated that the incidence rate of cervical cancer in vaccinated women younger than 31 years was significantly lower than that in unvaccinated women, with the lowest incidence rate among women vaccinated before age 17.

Lastly, as HPV vaccines become more prevalent worldwide, public health research has been using modeling studies to predict the long-term effectiveness and impact of HPV vaccination in the community. Early data suggest that even in models where only girls are vaccinated, and with a low vaccination rate of 20%, herd effects could be achieved. In models where high coverage of HPV vaccination is achieved in both boys and girls, data suggest that it may even be possible to eliminate high-risk HPV types.

Although a therapeutic HPV vaccine that can treat HPV-associated precancerous lesions or cervical cancer is not yet available, several clinical trials are currently under way. More importantly, emerging evidence has suggested that there may be benefits for women undergoing surgical treatment for HPV-related disease in receiving adjuvant vaccination with the currently available prophylactic HPV vaccine after primary treatment. For this population, studies have revealed a reduction in risk of recurrent lesions (CIN 2+) caused by HPV-16/18 after adjuvant vaccination.

Currently, ACOG and the Centers for Disease Control and Prevention have recommended that the HPV vaccine could be offered to those aged 27 to 45 years who had not been previously vaccinated based on shared clinical decision-making.

 Although vaccine efficacy and effectiveness are lower in women in this age group, HPV vaccination may still offer benefits for
specific populations.

In May 2018, the World Health Organization Director-General announced a global call for action to eliminate cervical cancer.

 The HPV vaccine, shown to be safe and highly effective, especially when administered at an early age prior to initiation of sexual activity, is a critical component of the strategy to achieve this goal. High rates of HPV immunization will also have important effects on other HPV-associated cancers. In addition to continued investigation into the efficacy and effectiveness of single-dose vaccines, efforts to address vaccine hesitancy and improve access to HPV vaccination are critical to achieve the goal of lowering barriers to vaccination worldwide.

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Articles

Deep dive into HPV vaccines

You can reach her a lcarr@mjhlifesciences.com.

 for many a comforting tradition of order, back-to-school supplies (unbelievably relaxing to many) and new beginnings. For senior medical students and residents, it is a time of opportunity, new potential, and fresh beginnings. As we look at the field of resident positions in obstetrics and gynecology, it is clear that not only have there been new positions growing for the field, but there has also been growing interest from the medical profession 

As I listen to the medical students interested in obstetrics and gynecology, preparing their chair letters, not only do they provide the typical reasons—a mixture of medicine and surgery, the ability to follow a patient over their life course, able to capture all of medicine in one field, present for life events vital for a critical event for a patient, and able to care for a patient in a vulnerable time—they have also highlighted the importance to support women and families, to provide needed care, and to participate in critical life events. The current generation of enthusiastic students entering our field have a lens to equity that we did not yet own at a similar time in our lives.

These observations give me hope for our specialty. I have seen interest in obstetrics and gynecology increase despite the COVID-19 pandemic and political situations. Many students voice an interest in not only in the intersection of surgery and medicine and continuums of care, but also the importance of supporting women and families. Their passion and excitement are infectious.

I think back to my decisions—I was torn between surgery and obstetrics and gynecology. This, on the background of my parents telling me to go into any field except obstetrics and gynecology due to the litigation and malpractice issues, but that was a long time ago. As I recognized, as do many students, the opportunities in obstetrics and gynecology are huge, as are the ability to practice both medicine and surgery. Furthermore, there is the opportunity for pure joy, which I reckon is limited in other fields. We tend to remember who delivered our baby—not so much who controlled blood glucose or a fixed a broken bone. We have the opportunity to be present at a time that is vital and critical in life.

As the leaves begin to change, and our students consider their choices, I encourage you to reflect on your reasons to pursue obstetrics and gynecology, and on the field’s importance— not just for you, but for your patients and for their families—and reconnect with your passions. 

Catherine Spong,editor in chief, is professor and vice chair in the Department of Obstetrics and Gynecology and Chief of the Division of Maternal-Fetal Medicine at UT Southwestern Medical Center in Dallas. She holds the Gillette Professorship of Obstetrics and Gynecology.

1. Results and Data 2022 Main Residency Match. The National Residency Match Program. May 2022. Accessed September 7, 2022. https://www.nrmp.org/wp-content/uploads/2022/05/2022-Main-Match-Results-and-Data_Final.pdf

Why obstetrics and gynecology is seeing an increase in applicants

A rising interest: Why obstetrics and gynecology is seeing an increase in applicants

Case. SL is a 14.5-year-old girl with heavy periods, dysmenorrhea, and acne seeking menstrual management. Her medical history includes 2 traumatic lifetime upper-extremity fractures and lactose intolerance. Menarche occurred at 12.5 years of age and periods occur every 27 to 32 days, and she routinely misses a few days of school each month because of her bothersome periods. SL takes no medications, including herbal agents or supplements. SL’s mother also had heavy, painful periods as a teen that improved as she got older. She was also recently diagnosed with osteopenia. SL has a boyfriend of 5 months and she confidentially shares that she would like contraception “just in case.” Her mother is open to SL starting a hormonal agent to improve her periods. They ask you what her options are.

SL’s story is not atypical. In taking a patient-centered, reproductive justice approach to contraceptive counseling, all options should be offered to SL without provider bias. Of course, there are many prescribing considerations for any adolescent. Clinicians must assess for medical contraindications to contraceptive use while also counseling patients about agent efficacy, potential side effects, confidentiality, access, and ease of and duration of use. Patients and guardians often ask about the potential long-term effects of contraceptive use on fertility and cancer risk, yet rarely ask about the potential skeletal impacts of any given contraceptive. However, clinicians should consider and discuss what is known about the bone health implications of hormonal contraceptive use in adolescence

 given that (1) 40% to 60% of one’s adult bone mass is accrued in adolescence; (2) a 10% increase in bone mass accrual during adolescence can potentially reduce adult fracture risk by 50%; and (3) Medicare cost estimates in the United States related to adult osteoporosis and fracture care exceed $50 billion dollars annually, including indirect costs such as productivity loss and caregiving.

Collagen and noncollagenous proteins form an organic matrix upon which bone mineral, composed primarily of calcium and phosphate, is deposited to form bone. Osteoblasts, osteoclasts, and osteocytes are the cells responsible for forming and resorbing bone, as bones grow in length and diameter, increase in bone mineral density (BMD), change shape, and respond to the daily insults of childhood and adolescence, an overall process known as bone remodeling.6 Bone mass (BM) has the potential to accrue throughout childhood and into young adulthood to a genetically determine peak bone mass (PBM), at which time the skeleton has reached its adult form and a stable state of bone mineral content. While 60% to 80% of one’s potential PBM is genetically predetermined, there are extrinsic factors that can negatively impact attaining optimal PBM, including chronic illness, medication exposure, substan

ce use, physical inactivity, nutritional deficits, and abnormal hormonal milieu.7,8

Maximal rates of BM accrual occur during the dynamic phase of puberty associated with peak height velocity driven by multiple hormones including, but not limited to, sex steroids, growth hormone (GH), and insulin-like growth factor-1 (IGF-1). Estrogen is particularly influential with estrogen receptors found on all skeletal cell types. Estrogen promotes the survival of osteoblasts, the bone building cells, and has a pro-apoptotic effect on osteoclasts, the cells responsible for bone resorption. Net BM accrual depends upon the balance between formation and resorption. During adolescence, bone formation should exceed bone resorption. It is suggested that by late adolescence, over 90% of one’s PBM has been attained.

Notably, estrogen also influences the pubertal growth spurt via the
GH/IGF-1 axis as well as growth plate closure and the cessation of linear growth.

 Given the importance of estrogen in bone physiology, any conditions or treatments altering physiologic estrogen production can negatively impact bone health.

The best clinical indicator of bone health is fracture history. Individuals with a history of fracture resulting from low-impact mechanisms of injury should raise concern for skeletal fragility and warrant a bone health evaluation. While adolescent fractures are not uncommon, with risk estimates ranging from 6% to 40% for girls up to aged 19 years, few pediatric studies evaluate fracture incidence as a primary study end point.

 Dual-energy x-ray absorptiometry (DXA) is the clinical and research tool most commonly used to assess BMD, acting as a surrogate marker of bone health. An adolescent’s BMD, as measured by DXA, is compared to a normative database of age- and sex-matched peers to generate a Z-score. A Z-score of 0 suggests average BMD for age, while a Z-score of –2.0 or less means that the adolescent’s BMD is 2 or more standard deviations lower than the average BMD of age- and sex-matched peers in the comparative database. BMD accounts for the majority of bone strength with the primary cause of adult osteoporotic fracture being reduced BMD from age-related bone loss and/or a failure to achieve optimal PBM by young adulthood

 Unlike measures of height and weight, obtained frequently in childhood and adolescence, BMD measures by DXA are not routinely tracked over time in otherwise healthy individuals. Therefore, for most healthy children and adolescents it is not possible to know their BMD trajectory toward their PBM. Importantly, per the International Society for Clinical Densitometry, “In patients with primary bone disease, or at risk for secondary bone disease, a DXA should be performed when the patient may benefit from interventions to decrease their elevated risk of a clinically significant fracture, and the DXA results will influence that management,” meaning a DXA is warranted only if its results will inform clinical decision-making.

The risks and benefits associated with the medical care we provide should be weighed and discussed with patients and, when appropriate, with their caregivers. From a pure bone health perspective, allowing the body to do what the body naturally does best is physiologically ideal. This includes supporting a normally functioning hypothalamic-pituitary-ovarian (HPO) axis. Many hormonal contraceptive agents prevent pregnancy and/or alter menstrual patterns by altering this HPO axis. Therefore, such hormonal contraceptive agents have the potential to negatively impact BM accrual in adolescence. Scientifically determining such impact is challenging on multiple levels given numerous available and changing contraceptive formulations, variable contraceptive adherence over time, frequently needed confidentiality in adolescent care, confounding extrinsic impacts on bone, and the inability to randomize and use placebo controls in adolescent contraceptive research. Therefore, available evidence must be interpreted in light of these limitations. Contraceptive options discussed will focus on what is known regarding their bone health impacts, which in no way is meant to diminish the significant roles these agents play in adolescent and adult reproductive health care. There is nothing more important than providing an individual with the tools they desire along their reproductive health journey, including menstrual management and contraception. It can also be argued that preventing the psychosocial impacts and known BM loss associated with 1 or more pregnancies and breastfeeding in the adolescent years may far outweigh any negative bone impacts of contraceptive agents themselves.

Depot medroxyprogesterone acetate (DMPA) is the only hormonal contraceptive agent with a black box warning from the US Food and Drug Administrative regarding its adverse effects on bone.

 This warning was informed by several studies demonstrating BM loss during DMPA use

The BM loss associated with DMPA is attributable primarily to its effects on the HPO axis resulting in a marked hypo-estrogenic state resulting in increased osteoclast activity at the level of bone. Interestingly, DMPA is also thought to bind to bone glucocorticoid receptors, thereby decreasing osteoblast proliferation.

 The overall effect favors bone resorption over formation, which is counter to normal adolescent bone physiology. Of note, studies show that BM loss is most significant in the first year of use and is at least partially reversible following DMPA cessation.

 In older adolescents and adult women who have achieved or nearly achieved PBM, this is reassuring. However, in younger adolescents tasked with gaining considerable BM over several years, the implications of BM loss on future PBM potential are likely more significant. It is unlikely that younger adolescents treated with DMPA for prolonged periods of time attain their genetically predetermined PBM following cessation of DMPA. In regard to fracture risk, in a case-control study of adult DMPA users, there was an association between fracture and prolonged current and prior DMPA use; however, similar studies have not be conducted in adolescents who have very different bone physiology.

 Despite such concerns, an individual’s DMPA use should not be time-limited if it is the best option for them and there is no formal recommendation to assess bone density in DMPA users.

 Lastly, in a convenience sample of older adolescents and young adults with cerebral palsy, there was no difference in BMD Z-scores by DXA in those with and without DMPA exposure. The authors concluded that this population with known BMD concerns should not be denied access to DMPA if it is the best option for them per patient-centered decision-making—a relevant conclusion for all patients.

Contraceptive Implants and Hormonal Intrauterine Devices

There have been few studies regarding the bone health impacts of long-acting, reversible contraceptive (LARC) methods in adolescents. Cromer et al prospectively assessed vertebral BMD changes in adolescent controls (n =17) and users of the NORPLANT implant system (n = 7) at 1 year and again at 2 years (n = 4 controls, n = 3 Norplant users).

Both groups were of similar age (15.2 years vs 15.5 years for Norplant users and controls, respectively). Reassuringly, BM accrual was similar over time in both groups. The authors propose that estrogen levels are not suppressed as much with this contraceptive implant as they are with DMPA. Such an estrogen threshold hypothesis has been supported by numerous studies and reviewed by Hadji et al in a paper regarding the bone health effects of progestins.26 Additional studies evaluating the 68-mg etonogestrel implant Implanon and the 75-mg levonorgestrel implant Jadelle was primarily conducted in adults. Evidence suggested a reduction in BMD at the midshaft ulna with BMD stability at the distal radius over 18 months of implant use.

 When comparing BMD change in adult women with Implanon vs a nonhormonal intrauterine device (IUD), there were gains in BM in both groups at the spine. Mean estradiol levels were notably higher in the Implanon cohort at all measured time points over 2 years. This is reassuring when considering how important estradiol is for BM accrual in adolescence. It is important to note that routine clinical practice recommendations do not include obtaining DXA scans or estradiol levels in implant users.

There are no studies of the BMD impacts of hormonal IUDs in adolescents. Hormonal IUDs do not significantly suppress endogenous estrogen production. The amenorrhea that is frequently achieved with hormonal IUDs is likely secondary to direct endometrial effects rather than to significant HPO axis suppression.= In a cross-sectional study of adults using the 52-mg levonorgestrel IUD Mirena, there was no difference in forearm BMD compared with adults using a nonhormonal IUD.

 In this same cohort followed prospectively, forearm BMD was stable over time.

 Importantly, in case-control analysis, there is no association between hormonal IUD use and fracture, and some evidence supports a reduced fracture risk in hormonal IUD users.

The bone health impact of progestin-only pills (POPs) in adolescents is similarly understudied. Once again, referring to the estrogen threshold hypothesis, POPs likely do not suppress the HPO axis enough to lower estrogen levels below a threshold that would be harmful to bone.26 That said, whether a young adolescent would accrue as much BM on POP therapy compared with no therapy at all is unknown. Importantly, there are no known associations between fracture incidence and POP use.

Combined hormonal contraceptives (CHCs) similarly exert their contraceptive and menstrual management impacts by altering the HPO axis, resulting in suppression of endogenous ovarian estradiol production, although not to the extent that DMPA does. Additionally, combined oral contraceptive (COC) use negatively impacts the liver’s production of IGF-1 and is associated with elevated biological markers of bone resorption.31,32 The demonstrated impact of CHCs on adolescent bone health is challenged by multiple available drug formulations and a lack of randomized, placebo-controlled trials. Additionally, studies are flawed by the fact that control groups are often younger than subjects on COCs, and early adolescent bone physiology is drastically different from that of later adolescence, making meaningful conclusions about BM change between cases and controls difficult. All totaled, studies and systematic reviews suggest that treating adolescents with COCs containing ≥ 30 μg ethinyl estradiol (EE) may support bone health better than low-dose (≤ 2-μg EE) pills.15,19,30,32-36 Additionally, the greatest impairment of COC use on BM accrual is thought to be within the first few years following menarche when BM accrual is most significant.32,37 Of note, in a large retrospective study of women from the United Kingdom with COC use, fracture incidence was lower in those who had used COCs compared with those who had not, and longer duration of COC use was associated with lower
fracture incidence.38

Very few studies have evaluated the bone health impacts of contraceptive patches and vaginal rings. Massaro et al assessed spinal BMD in young adult women using a contraceptive patch (norelgestromin 150 µg and
EE 20 µg) vs a vaginal ring (etonogestrel 120 µg with EE 15 µg) and found no significant change in BMD over 1 year in either group.39 A pilot study with 5 adolescents using the contraceptive patch and 5 similarly aged controls found no change in BM over 1 year in the patch users compared with a nearly 4% increase in total-body bone mineral content in controls.40 IGF-1 levels were notably the same in the patch users compared with the controls.

Regardless of contraceptive used, all clinicians should be counseling adolescents to optimize their bone health. This includes engaging in weight-bearing activity as is possible; avoiding substance use; and having a healthy, adequate, and well-balanced diet. Very few adolescents achieve the recommended daily allowance (RDA) for calcium and vitamin D.41 A healthy individual will maintain blood calcium levels in a normal range at the expense of their bone density if they are not ingesting adequate calcium or are unable to adequately absorb the calcium they do ingest as a result of vitamin D deficiency. The RDA for calcium is 1300 mg daily for 9 to 18-year-olds, which is slightly more than four 8-ounce glasses of milk each day. Since calcium is not easily absorbed in large quantities (up to 500 mg is absorbed at a time), intake must also be spread throughout the day, whether through dietary intake or supplements. Reviewing the Center for Young Women’s Health resource on calcium intake with patients and families can be eye-opening. Similarly, it is very hard to meet the RDA for vitamin D through diet alone, which is why vitamin D deficiency is common.42 Although there are no recommendations to check vitamin D levels in otherwise healthy individuals, meeting the RDA for vitamin D is necessary to support overall adolescent bone health, and some individuals may need more than the RDA to achieve vitamin D sufficiency.43

After reviewing her options, SL is most interested in pursuing a hormonal IUD for menstrual management and for contraception when she needs it. Her mother was concerned about the potential bone health impacts of the other contraceptive agents given her own diagnosis of osteopenia. SL likes that she wouldn’t have to remember to take a medication. Given her lactose intolerance, she avoids dairy, and after reviewing the youngwomenshealth.org website, she and her mother plan to incorporate more calcium and vitamin D into her diet and/or through supplements to support healthy bones.


Optimizing child and adolescent bone health can reduce morbidity and mortality associated with adult osteoporosis, so considering and discussing bone health with adolescents is essential. Unfortunately, it is challenging to fully understanding the impacts of all available hormonal contraceptives on adolescent bone health given inherent limitations in research to date, yet it is our job to use available evidence to inform our patient-centered approach to reproductive health care.

The following key points should be considered:

DMPA is associated with BM loss during use. Prolonged use in the first few years following menarche could have the greatest negative impact on bone. It is reassuring that there is substantial BM recovery following DMPA cessation; however, prolonged use in younger adolescents may impair PBM. Prolonged DMPA use may also be associated with adult fracture.

POPs and hormonal IUDs do not substantially suppress the HPO axis and therefore are thought to have no ill effect on BM, although studies in adolescents, especially young adolescents, are not available.

Hormonal implants are generally thought to be safe for bone, although whether a young adolescent would reach their genetically determined PBM while using a contraceptive implant is not known.

Individuals using COCs have demonstrated BM gain during adolescence, although such accrual may be less than what they would have seen without COC treatment. When used, a COC containing ≥ 30 µg EE is likely preferred, if tolerated, from a purely bone health perspective. There is too little evidence regarding the bone impact of vaginal rings and contraceptive patches in adolescents to inform 
a recommendation.

Engaging in weight-bearing activities as is feasible and ingesting adequate nutrition including meeting the RDA for calcium and vitamin D intakes are important for all adolescents.

The contraceptive agent that is best for a given adolescent is the 1 that they prefer once they have been informed about their use, efficacy, side effects, and risks, and once issues of access, confidentiality, and medical eligibility have been considered. Such information can be overwhelming for patients and caregivers. Clinicians are tasked with the important job of conveying this information in an understandable way without personal bias to support adolescents along their reproductive health care journey. 

Gordon RJ, Gordon CM. Adolescents and bone health. 

. 2020;63(3):504-511. doi:10.1097/GRF.0000000000000548

Golden NH. Bones and birth control in adolescent girls. 

. 2020;33(3):249-254. doi:10.1016/j.jpag.2020.01.003

Lahoti A, Yu C, Brar PC, et al. An endocrine perspective on menstrual suppression for adolescents: achieving good suppression while optimizing bone health. 

. 2021;34(11):1355-1369. doi:10.1515/jpem-2020-0539

Rocca ML, Palumbo AR, Bitonti G, Brisinda C, DI Carlo C. Bone health and hormonal contraception. 

. 2021;73(6):678-696. doi:10.23736/S2724-606X.20.04688-2

Hansen D, Pelizzari P, Pyenson B. Medicare cost of osteoporotic fractures – 2021 updated report: The clinical and cost burden of fractures associated with osteoporosis. March 2021. Accessed June 10, 2022.

https://www.milliman.com/en/insight/-/media/milliman/pdfs/2021-articles/3-30-21-Medicare-Cost-Osteoporotic-Fractures.ashx

. In: Pitts S, Gordon CM, eds. A Practice Approach to Adolescent Bone Health. Cham, Switzerland: Springer International Publishing; 2018; 11-25.

Loud KJ. Optimizing bone mass accrual in health adolescents. In: Pitts S, Gordon CM, eds. A Practice Approach to Adolescent Bone Health. Cham, Switzerland: Springer International Publishing; 2018; 1-9.

Weaver CM, Gordon CM, Janz KF, et al. The National Osteoporosis Foundation's position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations. 

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