EXPLORE PAST ISSUES
Menopause
Vol. 19 No 1 | Autumn 2017
Feature
Body-identical hormone therapy
A/Prof John Eden
MB BS, MD, FRANZCOG, FRCOG, CREI

Some women passing through the menopause transition suffer severe sweats and flushes or other menopausal symptoms, and while menopausal hormone therapy (MHT) is by far the most effective treatment, many are fearful of using it. Every doctor who treats menopausal women knows that the ‘big issue’ around MHT usage is breast cancer risk. When the Women’s Health Initiative (WHI) study dramatically released its initial results to the world media in 2002, this resulted in headlines here in Australia such as ‘Stop your HRT and see your doctor’ (Daily Telegraph lead page 10 July 2002). Many now incorrectly believe that all MHTs cause breast cancer.

For example, in WHI, there was a difference in breast cancer risk between the combined arm (eight extra breast cancers per 10 000 per year after five years)1 and the oestrogen-only arm (significantly reduced risk of intraductal carcinoma compared with placebo).2 A large randomised controlled trial (RCT) of tibolone also showed a significantly reduced risk of breast cancer, compared with placebo.3 Many women want to use ‘natural hormones’. Compounded MHT, often called bio-identical hormone therapy (BHT) is currently being used by thousands of Australian women, despite the risks of using a treatment that has no formal quality control or safety studies. BHT has been reviewed by a number of scientific bodies and largely rejected on safety grounds.4 5

Body-identical hormone replacement therapy has been suggested by some in Europe.6 This uses pharmaceuticals that contain real human hormones such as oestradiol (E2) and progesterone (P4), rather than conjugated equine oestrogens, tibolone or norethisterone (NE). In Australia, body-identical oestrogens have been available for many years. These include E2 patches, oral tablets or transdermal gel, as well as E2 pessaries and oestriol cream.

Until recently, synthetic progestins had to be used to protect the endometrium and studies such as WHI have confirmed that progestins seem to significantly contribute to the increased risk of breast cancer seen with combined MHT and likely negate some of the cardiovascular benefits of oestrogen.

Progesterone has been available in Australia as a pessary for some years (mostly for luteal phase support), but rarely used as part of MHT. Micronised progesterone (mP4) became available as a gel cap for oral use (Prometrium, Besins) from 1 September 2016. Micronised progesterone combined with E2 has been used in Europe for many years. This article will focus on the safety aspects of MHT containing mP4.

Oestradiol

E2 has long been available in Australia, and for many healthy women aged 60 years or younger, oral E2 is usually safe. Oral E2 is available as a single-agent tablet (for example, Progynova 1mg, 2mg) or in combination with synthetic progestins (for example, Femoston range).

For those over 60 years of age or at risk of thrombotic episodes (for example, history of DVT, thrombophilia), transdermal E2 should be considered (patches or gel) as first-line treatment. Oral E2 undergoes hepatic first-pass with activation of clotting factors in contrast to transdermal therapies, which do not.7 Clinical trials also confirm that oral E2 oestrogens including E2 are linked to increasing risk with age of DVT, stroke and pulmonary embolism, unlike transdermal E2 that appears to have minimal or no effect on the risk of venous and arterial thrombosis.8 Transdermal E2 is available as patches (for example, Estradot, Estraderm, Climara) or gel (Sandrena) or in a CombiPatch with NE as the progestin (Estalis range).

Vaginal oestrogens are best delivered into the anterior vaginal compartment, which has vascular and lymphatic connections with the vulva, clitoris and bladder.9 10 As will be discussed later, the posterior vagina can be used as a delivery system for the uterus.

Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is an adrenal prohormone having no biological activity of its own; however, in those tissues that have the suitable enzyme systems (for example, the vagina) DHEA can be converted into oestrogens and androgens. Reviews and RCTs have shown that oral DHEA appears to be devoid of any clinically relevant action.12 In contrast, vaginal DHEA appears to oestrogenise the vagina without any systemic effect.13

Testosterone

Serum levels of both DHEA and testosterone fall with age. However, unlike DHEA, testosterone replacement may have a role when a woman presents with fatigue and loss of sex drive, in association with a low total- or free-testosterone level. Other causes, such as thyroid disease, iron deficiency and relationship issues, need to be excluded.

This topic has been reviewed elsewhere.14 The only pharmaceutical grade testosterone product for women available in Australia is AndroFeme (Lawley Pharmaceuticals, WA). The starting dose is 0.5cc daily, rubbed into the skin of the thigh or buttock; with a therapeutic goal of a Free Androgen Index (FAI = T X 100 / SHBG) between 4–7 per cent. Typically, around two-thirds of women have an improvement in energy and sex drive over about six months.15 16

If E2 is given concomitantly, transdermal E2 is preferred. Oral E2 may increase serum levels of the hepatic derived, sex-hormone binding protein (SHBG) that will, in turn, reduce free testosterone levels.

Progesterone

Two micronised progesterone products were recently released in Australia – Prometrium 100mg and Utrogestan 200mg. These two products have identical specifications but different dosages; in clinical practice both products can be used orally or vaginally. Micronisation improves gut and vaginal absorption of the product. Oripro vaginal pessaries 100mg and 200mg and Crinone vaginal gel 8% (90mg) are also available in Australia.

Clinical trials have shown that the endometrial protective dose of oral mP4 is 200mg cyclical or 100mg daily, at least when used with E2 patches 25–50µg daily (or conjugated equine oestrogens [CEE] 0.625mg daily).17 18 19 These studies also demonstrated that mP4 did not attenuate the cardiovascular benefits of oestrogens, unlike synthetic progestins. Oral mP4 is very well tolerated with few patients having side effects, although mild sedation can occur with commencement of therapy and, as such, should be taken at night.20 A small minority may develop bloating or mood swings. As will be discussed shortly, these patients can switch to the vaginal route and avoid these side effects. In contrast, around 10 per cent of women using progestins develop side effects, such as bloating, mood swings and even depression.21

The vagina as a delivery system has been reviewed.22 23 The posterior vagina has lymphatic and circulatory connections with the uterus and vaginal P4 is particularly well absorbed into the uterus. Clinical trials have shown that if low doses of E2 are given transdermally (for example, 25µg E2 patch or a sachet of Sandrena gel daily) then doses of vaginal progesterone as low as 100mg two to three times a week in divided doses are effective for endometrial protection. Stute and colleagues have recently reviewed this subject.24

Breast effects of MHT containing mP4

The E3N-EPIC Study is a large prospective cohort study investigating women born between 1925 and 1950 (n=98 997).25 Breast cancer risk factors were reviewed in 54 548 postmenopausal women who had never used HRT before entering into the trial. Over the study period of six years, 958 primary breast cancers were detected. Those who used HRT took it for an average of 2.8 years. Those using E2 alone (hysterectomised patients) and those using E2 and mP4 did not have an increased risk of breast cancer, in contrast to those using oestrogen and synthetic progestins, who had a significantly increased risk of developing the disease (RR 1.4 [95% CI 1.2–1.7]).

A recent systematic review examining the breast cancer risk associated with progestins and mP4 26 has confirmed these results. MHT regimens using mP4 were associated with a significantly lower risk of breast cancer than those using MHT therapies that included a synthetic progestin (RR 0.67; 95% CI 0.55–0.81). These clinical trial results are consistent with laboratory data, suggesting that progestins have adverse effects on breast cells in culture and in animal models, unlike P4 which seems to be neutral in terms of breast cancer promotion in the lab.27

Discussion

Body-identical MHT is preferred by many women, as shown by the number of Australian women using compounded, untested ‘bio-identical HT’. With the arrival of oral mP4 to Australian shores, these women and their doctors finally have access to a tested, pharmaceutical-grade MHT.

However, there is still a role for other therapies. The Mirena device can very effectively control the heavy frequent periods associated with the perimenopause and can be combined with oral or transdermal E2. Cyclical MHTs, or even low-dose contraceptive pills, can be very helpful for some women to help them transit their perimenopause. For many postmenopausal women, whose only problem is vulvovaginal dryness, topical oestrogens are very effective and safe.

After several decades of research, it is clear that the diverse MHTs have different risk to benefit ratios. For those who have had a hysterectomy, unopposed transdermal E2 appears particularly safe. For women with an intact uterus, body-identical MHT containing mP4 appears to be a safe, tested and effective treatment.

References

  1. WHI Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002;288(3):321-33.
  2. WHI investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295(14):1647-57.
  3. Cummings SR, Ettinger B, Delmas PD, et al. The effects of Tibolone in older postmenopausal women. N Engl J Med. 2008; 359: 697-708.
  4. Baber RJ, Panay N, Fenton A. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric. 2016;19(2):109-50.Baber RJ, Panay N, Fenton A. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric. 2016;19(2):109-50.
  5. Cirgliano, M. Bioidentical Hormone Therapy: A Review of the Evidence. J Women Health. 2007;16(5):600-31.
  6. Panay N. Body identical hormone replacement. Post Reprod Health. 2014;20:69-72.
  7. Canonico M, Plu-Bureau G, Lowe GDO, Scarabin P-Y. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008; 336(7655):1227-31.
  8. Canonico M, Plu-Bureau G, Lowe GDO, Scarabin P-Y. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008; 336(7655):1227-31.
  9. Cicinelli E. Intravaginal oestrogen and progestin administration: advantages and disadvantages. Best Pract Res Clin Obstet Gynaecol. 2007;22(2):391-405.
  10. Cicinelli E, Rubini G, De Ziegler D, et al. Absorption and preferential vagina-to-uterus distribution after vaginal administration of 99mTc-pertechnetate in postmenopausal women. Fert Steril. 2001;76(6):1108-12.
  11. 11Eden, J. DHEA replacement for postmenopausal women: placebo or panacea? Climacteric. 2015;18(4):439-40.
  12. Eden, J. DHEA replacement for postmenopausal women: placebo or panacea? Climacteric. 2015;18(4):439-40.
  13. Davis SR, Braunstein GD. Efficacy and safety of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. J Sex Med. 2012;12(9):1134-1148.
  14. Davis SR, Braunstein GD. Efficacy and safety of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. J Sex Med. 2012;12(9):1134-1148.
  15. Goldstat R, Briganti E, Tran J, et al. Transdermal testosterone therapy improves well-being, mood, and sexual function in premenopausal women. Menopause. 2003;10(5):390-8.
  16. Writing group for PEPI. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. JAMA. 1996;275:370-5.
  17. Cicinelli E, de Zigler D, Alfonso R, et al. Endometrial effects, bleeding control, and compliance with a new postmenopausal hormone therapy regimen based on transdermal oestradiol gel and every-other-day vaginal progesterone in capsules: a 3 year pilot study. Fert Steril. 2005;83(6):1859-63.15
  18. Stute P, Neulen J, Wildt L. The impact of micronized progesterone on the endometrium: a systematic review. Climacteric. 2016;19(4):316-28.
  19. Sheriff K. Hormone Therapy: Monitoring Effects and Side Effects in Hormone Therapy: A clinical handbook. New York: Springer-Verlag; 2013. 79-83.
  20. Sheriff K. Hormone Therapy: Monitoring Effects and Side Effects in Hormone Therapy: A clinical handbook. New York: Springer-Verlag; 2013. 79-83.
  21. Cicinelli E. Intravaginal oestrogen and progestin administration: advantages and disadvantages. Best Pract Res Clin Obstet Gynaecol. 2007;22(2):391-405.9
  22. Cicinelli E, Rubini G, De Ziegler D, et al. Absorption and preferential vagina-to-uterus distribution after vaginal administration of 99mTc-pertechnetate in postmenopausal women. Fert Steril. 2001;76(6):1108-12.
  23. Stute P, Neulen J, Wildt L. The impact of micronized progesterone on the endometrium: a systematic review. Climacteric. 2016;19(4):316-28.
  24. Fournier A, Berrino F, Riboli E, et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114(3):448-54.
  25. Asi N, Mohammed K, Haydour Q, et al. Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis. Systematic Reviews. 2016; 5:121-9.
  26. Campagnoli C, Clavel-Chapelon F, Kaaks R, et al. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Mole Biol. 2005; 96: 95-108.

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