CATIE News

• Premature cessation of menstruation can occur in some women living with HIV
• A Vancouver study identified opioid and tobacco use as relevant risk factors
• This condition may contribute to the thinning of bones and the risk of fractures

Scientists at the University of British Columbia and the Oak Tree Clinic in Vancouver collaborated on a study to explore the issue of premature cessation of menstruation during reproductive years—a condition called amenorrhea. The study enrolled both HIV-positive and HIV-negative women of similar sociocultural background. The scientists defined amenorrhea as a past or present lack of periods for more than one year that occurred before the age of 45 and was unrelated to pregnancy, breastfeeding, surgery or use of hormonal contraception. Amenorrhea is different from menopause.

The scientists collected and analysed data from 258 women and found that prolonged amenorrhea occurred in 21% of HIV-positive and 9% of HIV-negative women. Furthermore, amenorrhea was linked to significantly reduced bone density in the hips. The scientists concluded that prolonged amenorrhea is another risk factor for osteoporosis in HIV-positive women. Based on their findings, they provided recommendations to reduce the risk of amenorrhea in this population.

Study details

Scientists recruited 129 HIV-positive and 129 HIV-negative women for this study. All participants were adults and completed detailed surveys about menstrual patterns, bone health and other issues. They also underwent low dose X-ray scan (DEXA) to assess bone density.

The average profile of all the women upon entering the study was as follows:

• age – 45 years
• main ethno-cultural groups: white – 56%; Indigenous – 9%; African/Caribbean/Black – 9%; East Asian – 7%; South Asian – 5%
• co-infection with hepatitis C virus (HCV) – 23%
• current calcium supplementation – 23%
• current vitamin D supplementation – 34%
• current or past tobacco use – 50%
• current or past alcohol use – 38%
• current or past use of opioids – 21%

HIV-specific measures:

• proportion with an undetectable viral load (less than 40 copies/mL) – 78%
• current CD4+ cell count – 560 cells/mm³
• lowest-ever CD4+ cell count – 180 cells/mm³
• past use of tenofovir DF – 80%

A note about amenorrhea

There are two main types of amenorrhea:

• primary amenorrhea – when a girl has not started having periods
• secondary amenorrhea – the absence of periods in girls and women who had previously been having periods

The Vancouver scientists focused on secondary amenorrhea, which we simply refer to as amenorrhea in this CATIE News bulletin.

Results—Amenorrhea

Key findings:

• Amenorrhea was significantly more common in HIV-positive women (21%) than in HIV-negative women (9%).
• On average, amenorrhea first occurred at the age of 26.
• HIV-positive women were more likely to have thinner bones compared to HIV-negative women.
• Women who had amenorrhea had reduced bone density in the hips regardless of HIV status. However, HIV-positive women with amenorrhea had even lower hip bone density than HIV-negative women with amenorrhea.

Fracture distribution

The proportions of women with fractures were as follows:

• HIV-positive women – 4%
• HIV-negative women – 5%

Focus on HIV-positive women

The scientists noted that some risk factors for amenorrhea—such as very low or very high body mass index (BMI), severe liver injury, exposure to anti-psychotic medicines—were similarly distributed between the HIV-positive and HIV-negative groups. Therefore, these factors were unlikely to be the major drivers of the difference in rates of amenorrhea seen in this study.

However, the scientists stated that HIV-positive women with amenorrhea “had significantly higher” rates of the following possible amenorrhea risk factors:

• HCV co-infection
• tobacco use
• opioid use (both prescribed and non-prescribed)

Focus on opioids

The scientists stated that the use of opioids “was particularly high” among HIV-positive women in the study. For instance, “63% of [HIV-positive women] experiencing prolonged amenorrhea indicated past or present opioid use/therapy compared to 22% of those without [amenorrhea].”

As part of the study, women were asked what they thought caused them to experience amenorrhea. Some of their answers were as follows:

• substance use or methadone – 41%
• menopause – 15%
• substance use/methadone and menopause – 14%

Lab tests of the blood samples from HIV-positive women who reported amenorrhea found that only four HIV-positive women had hormonal levels suggestive of early menopause or premature failure of the ovaries (a level of follicle-stimulating hormone of 25 IU/L or greater). Thus, opioids likely contributed to the development of amenorrhea.

Other factors

Positive factors that help maintain or even increase bone density include supplementation with calcium and vitamin D and hormone replacement therapy. Other factors can have a negative effect, reducing bone density, such as the following: use of corticosteroids, smoking and use of the anti-HIV drug tenofovir DF (in Atripla, Complera, Stribild, Truvada and generic formulations). The scientists found no significant differences in the distribution of these factors among HIV-positive women with or without amenorrhea.

Bear in mind

Based on the data they collected as well as other studies with HIV-positive women, the B.C. scientists stated that there may be multiple factors affecting the hormonal health of women in the present study. They singled out the following factors that likely increased the risk of amenorrhea:

• opioid use – this could have directly contributed to reduced levels of estrogen and/or progesterone. Sharing of equipment for substance use could have led to some, perhaps many, of the women becoming infected with HCV. This virus injures the liver. Over time, such injury could have affected the production of hormones that have an impact on bone health. Opioid use also could have led to transformation in the brains of participants—addiction—that caused them to prioritize substance use over what the scientists called “healthy nutrition and weight-bearing exercise.” These latter factors are known to play a role in maintaining bone density.
• tobacco use – this was relatively high in the study, with 66% of HIV-positive women reporting current or past use vs. 33% of HIV-negative women

A subgroup of women—those who have or had amenorrhea—are at high risk for bone thinning, particularly in the hips, and therefore they are also at risk for fractures. The scientists described the degree of bone thinning in HIV-positive women who have or had amenorrhea as “profound.” Such a degree of bone thinning has been historically linked to a 2.6-fold increased risk of fracture in HIV-negative women (data for large numbers of HIV-positive women are not available). HIV-positive women would have at least a similar risk of fractures, perhaps even higher given that risk factors for bone loss are generally greater among people with HIV.

The present study was cross-sectional in design, which means that data were captured at one point in time. The study was well designed with a comparison group of women who were socially and culturally similar to the HIV-positive women. Furthermore, the women in this study are representative of the distribution of HIV among women in British Columbia.

Reducing the risk of bone fractures in this population

The scientists stated that HIV-positive women who have or had amenorrhea “may benefit from earlier fracture risk investigation than is currently recommended [after menopause or a new fragility fracture]. Prompt recognition of abnormally low bone density may allow early initiation of effective therapy [among women who have or had amenorrhea] or preventative measures,” such as the following:

• hormone therapy
• screening and treatment for HCV infection
• referral to harm reduction organizations for women who use substances
• screening for eating disorders
• providing referrals for mental health support if necessary
• providing referrals for nutritional counselling
• facilitating smoking cessation
• reassessment of HIV treatment regimens that include tenofovir DF

In addition, the scientists recommended the “usual strategies” to prevent further bone loss, including the following:

• supplementation with calcium and vitamin D
• weight-bearing exercises

There are also medicines that can be prescribed to reduce the loss of bone density.

Resources

Irregular or absent periods – Society of Obstetricians and Gynecologists of Canada

Amenorrhea – Hormone Health Network (available in English only)

B.C. study finds that HIV-positive women are likely to have other health conditions – CATIE News

Traditional risk factors have a big impact on bone thinning in HIV-positive people – CATIE News

Canadian study examines why some women fall out of the HIV care cascade – CATIE News

Comparing substance use patterns among women in Canada – CATIE News

Delays in cervical cancer screening among some HIV-positive Canadian women – CATIE News

—Sean R. Hosein

REFERENCES:

1. King EM, Nesbitt A, Albert AYK, et al. Prolonged amenorrhea and low hip bone mineral density in women living with HIV—a controlled, cross-sectional study. Journal of Acquired Immune Deficiency Syndromes. 2020; in press.
2. Donaldson MA, Campbell AR, Albert AY, et al. Comorbidity and polypharmacy among women living with HIV in British Columbia. AIDS. 2019;33(15):2317–2326.
3. Cejtin HE, Evans CT, Greenblatt R, et al. Prolonged amenorrhea and resumption of menses in women with HIV. Journal of Women’s Health. 2018;27(12):1441–1448.
4. Castellini G, Lelli L, Cassioli E, et al. Relationships between eating disorder psychopathology, sexual hormones and sexual behaviours. Molecular and Cellular Endocrinology. 2019;497:110429.
5. Vuong C, Van Uum SH, O’Dell LE, et al. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocrine Reviews. 2010;31(1):98–132.
6. Thomsen MT, Wiegandt YL, Gelpi M, et al. Prevalence of and risk factors for low bone mineral density assessed by quantitative computed tomography in people living with HIV and uninfected controls. Journal of Acquired Immune Deficiency Syndromes. 2020;83(2):165–172.