Advancing Estrogen Replacement to Protect Bone Health in Young Women with Functional Hypothalamic Amenorrhea

Approximately 75% of young women with anorexia nervosa and up to 60% of female endurance athletes will develop menstrual dysfunction during their reproductive years, with significant and deleterious implications for bone health. Menstrual dysfunction in these conditions includes irregular to absent periods, and occurrence of menstrual dysfunction in the absence of organic pathology is termed functional hypothalamic amenorrhea (FHA). When providers recognize this red flag early, treatment can help these young women thrive.  

FHA is often the result of a state of energy deficit, when energy intake is insufficient to meet the needs of energy expenditure. When this happens, it doesn’t just disrupt menstrual cycles. It also disrupts other aspects of crucial development, including bone health. This is particularly a problem for adolescents.

“Maximal bone accrual typically occurs during adolescence.” Madhusmita Misra, MD, explains. “A consequence of energy deficit and menstrual dysfunction during this time is suboptimal peak bone mass, which reflects your bone ‘bank’ for your entire life and determines future fracture risk.”  

A Double Insult

Endocrine disruption caused by energy deficit affects bone health as follows:

1. There is an increase in hormones such as cortisol, ghrelin, and peptide YY, and a decrease in insulin-like growth factor-1 (IGF-1). During adolescence, rising levels of IGF-1 are essential for bone accrual as this hormone increases bone formation. Thus, reductions in IGF-1 lead to suboptimal bone density. Increases in cortisol and PYY decrease bone formation and increase bone loss.
2. The energy deficit state and several of these hormone imbalances also lead to a reduction of gonadotropin-releasing hormone (GnRH) secretion, which in turn causes low estrogen levels and FHA. Without estrogen, bone breakdown occurs more quickly, and bone accrual is again negatively impacted.

The result could be a young athlete sidelined by stress fractures as a consequence of low bone density, or a girl struggling with fragility fractures while doing their favorite activities.

Treating FHA Starts at the Cause

To help young people with FHA thrive, treatment must address problems on multiple levels through multiple disciplines.

FHA is primarily caused through one of three pathways:

• Disordered eating
• Extreme exercise
• Excessive stress

Apart from bone health, these three causes have other health effects, some catastrophic.

Anorexia nervosa, one of the more common causes of FHA, has the highest mortality rate of any psychiatric disorder. Bone density is just one piece of their health puzzle. At UVA Health Children’s, a patient with FHA from disordered eating works with dietitians, eating disorder specialists, mental health professionals, and care coordinators as part of their healthcare team.

“But even with weight regain, many still have residual bone deficits,” Misra shares. Which is why endocrine intervention is an important component of complete care for these patients.

Given how formative these years are for bone health, correcting these problems can’t wait.  

Improving Bone Health

Helping young patients overcome the underlying cause of their FHA by addressing energy status is crucial. However, during the critical years of bone development, additional interventions may be necessary early on, given that the window for intervention to optimize peak bone mass acquisition is small.  

Registered pediatric dietitians trained to work with young women with eating disorders and hyperexercising athletes help with crafting diets to meet their energy needs. Further, calcium and vitamin D supplementation is an easy place to start to optimize bone mineralization.

Additionally, FHA creates a low estrogen situation, which negatively impacts bone health. Finding the correct estrogen replacement therapy can help improve bone accrual.

Estrogen Therapies

“The most commonly used estrogen product in the market right now is the combined oral contraceptive pill. And so, initially people thought, pretty logically, that giving the oral contraceptive pill would be a good strategy to replace estrogen in these women,” Misra shares. “However, it turns out that this is just not effective in improving bone density in young women with FHA from anorexia nervosa or excessive exercise.”

Not all estrogen therapy is the same, however. Recently, Misra and her colleagues have found success with improving bone accrual in youth with FHA using the 17-beta estradiol patch. Estradiol is a bioidentical replacement for the body’s estrogen, rather than the synthetic hormone (ethinyl estradiol) found in the oral contraceptive pill.

Medication administered as a patch is absorbed through the skin into the bloodstream, bypassing the digestive system and liver. A reason why the combined oral contraceptive is not effective in improving bone density is because when given orally, ethinyl estradiol is first metabolized in the liver and reduces the production of IGF-1. In contrast, 17-beta estradiol given transdermally avoids this metabolism and IGF-1 levels are preserved.  Many women also prefer transdermal patches because of reduced side effects.

Isolating Variables

Does the transdermal patch perform better because of the delivery system (transdermal vs. oral), or the type of hormone (bioidentical vs. synthetic)? Or is it maybe a little bit of both?

In one of the clinical trials that Misra is currently running, FHA patients are given 1 of 3 forms of estrogen:

• 17-beta estradiol, in patch form
• 17-beta estradiol, in pill form
• Ethinyl estradiol, in patch form (a contraceptive patch)

If the 17-beta estradiol pill or the ethinyl estradiol patch are as effective as the 17-beta estradiol patch in improving bone health, this would allow for more options of estrogen replacement in women affected by FHA. This is also important because some women prefer the pill to the patch, and the transdermal 17-beta estradiol patch does not have contraceptive efficacy, while the ethinyl estradiol patch does provide contraception.

No matter which method and type of hormone they receive, it’s balanced by cyclic or continuous progestin to ensure that problems of unopposed estrogen exposure are avoided.

Adding a Bone Anabolic Agent

Further, because bone formation is so important for optimizing bone accrual, Misra and her colleagues are assessing the efficacy of a medication called romosozumab (which both increases bone formation and decreases bone loss) in improving bone density in young women with FHA.  This drug has been well studied in postmenopausal women and older men, with excellent results.

Menstrual Irregularities Offer Early Warning Signs

Menstrual cycles, and their absence, offer important clues to underlying health issues. In many cases, young females with FHA have defied stereotypical low weight presentations and presented at normal weight ranges. Without considering changes to their menstrual cycle, the problems of FHA may continue unchecked.

With better treatments emerging for long term concerns, like bone density, the benefits to early diagnosis continue to expand.