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Clinical case

MM is a 47-year-old journalist. She sought consultation for irregular periods, vasomotor symptoms, insomnia, low energy and libido and recent weight gain. She had a personal history of migraine, premenstrual syndrome and was heterozygous for Factor V Leiden. In her family history, the following events were reported: venous thromboembolism in her mother while on oral contraceptives, breast cancer in her sister, osteoporosis in two aunts. Lately, she had been having difficulty concentrating at work and was seeking a divorce from her husband. Before coming to our menopause clinic in London, the patient had a Levonorgestrel-releasing intrauterine system (IUS) inserted, but this induced a severe emotional reaction. MM stated “I went crazy”; she had the IUS removed within 48 hours. Afterwards, she was treated with a sequential combined patch and tablet regimen, with estradiol (E2) /norethisterone acetate (NETA). This treatment induced PMS symptoms and an acne eruption on her skin in the luteal phase. Moreover, none of these therapies improved her libido. She stopped the therapy and attended a compounded bioidentical (cBI) hormone therapy clinic, which claimed to offer “individualized” treatment, but MM had no response to treatment after three months, and her vaginal bleeding became chaotic. She, therefore, stopped cBI HT.

Our examination revealed BMI of 30, blood pressure of 158/87 mm Hg. A blood profile, day 3 hormone profile, pelvic ultrasound and DEXA scan were requested.

Results were as follows:

  • Fasting Insulin 26mIU/l (n<25) / BG 4.5mmol/l
  • Lipid Profile Cholesterol 5.6mmol/l LDL 3.5mmol/l
  • FSH 23iu/l
  • E2 70 pmol
  • Testosterone 0.4nmol/l, SHBG 98nmol/l
  • FAI (T x 100/SHBG = 0.5%)
  • Progesterone 1.2nmol
  • TFTS T4 12pmol/l TSH 3.9mIU/l
  • Pelvic US Endometrial thickness 4.2mm antral follicle count 5 Follicular Cyst 3 cm
  • DEXA scan T score-1.5 Lumbar Spine T score -1.2 Total Femur (osteopenia)

We prescribed the patient transdermal E2 cutaneous gel 1.0 mg sachets, micronized progesterone 2 x 100 mg/day per os from day 17 to day 28, Testosterone 5 mg / day 1% cream. The patient’s periods regulated, became lighter and shorter, vasomotor symptoms resolved and insomnia improved, especially when taking micronized progesterone at bedtime. Her libido, energy and “joie de vivre” were back after three months. She was in a new relationship and had achieved a job promotion! We then suggested using micronized progesterone continuously (100 mg) to achieve a no bleed regimen.

Discussion

Progestogens have a variety of effects apart from the one for which their use was intended, that of secretory transformation of the endometrium. Symptoms of fluid retention are produced by the sodium retaining effect of the renin-aldosterone system, which is triggered by the stimulation of mineralocorticoid receptors. Androgenic side effects such as acne and hirsutism are a problem of the testosterone-derived progestogens due to the stimulation of the androgen receptors [1]. Mood swings and PMS-like side effects result from the stimulation of the central nervous system progesterone receptors [1]. Furthermore, the Women’s Health Initiative and Million Women and French E3N Studies demonstrated an excess risk of breast cancer [2-4] in estrogen and progestogen users compared to estrogen alone. Subsequent studies have also shown that progestogens modulate VTE risk [5] and that progesterone and dydrogesterone are associated with lower risk then androgenic progestogens. Most menopause specialists still recommend the use of progestogens. However, we must seek improved ways of administering them in order to avoid side effects and minimize risks on the breast and cardiovascular system. Reducing the dose of the estrogen in ultra-low dose modern MHT can allow a significant reduction of progestogen dose, e.g. 0.5 mg estradiol with 0.1 norethisterone acetate or with 2.5 mg dydrogesterone; these combinations appear to maintain vasomotor benefits while minimizing side effects and potential risks [6-7]. The levonorgestrel intrauterine system (LNG IUS) reduces systemic progestogenic side effects by releasing the progestogen directly into the endometrium with low systemic levels. However, in severely progestogen intolerant women, even the low systemic levels of the 20 mcg LNG IUS can produce negative mood effects [8]. The lower dose LNG systems should be better for these women, but we lack safety data in MHT. Drospirenone is not only progesterone receptor-specific but has anti-androgenic and anti-mineralocorticoid properties; the former makes it useful for hirsutism and the latter for fluid retention and hypertension [9]. Progesterone receptor-specific progestogens, e.g. dydrogesterone and natural progesterone, have fewer side effects due to avoidance of the mineralocorticoid and androgen receptors [1]. Going forward, advances in the tissue-selective agents, the use of selective estrogen receptor modulators, TSECs and the progesterone receptor antagonists/modulators should also facilitate the specific targeting of the endometrium.

Nick Panay
Imperial College London, Women’s Health Research Centre, United Kingdom

References

  1. Schindler AE, Campagnoli C, Druckmann R, et al. Classification and pharmacology of progestins. Maturitas. 2008;61(1-2):171-180.
    https://pubmed.ncbi.nlm.nih.gov/19434889/
  2. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321–33
    https://pubmed.ncbi.nlm.nih.gov/12117397/
  3. Beral V. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003 Aug 9;362(9382):419-27.
    https://pubmed.ncbi.nlm.nih.gov/12927427/
  4. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study [published correction appears in Breast Cancer Res Treat. 2008 Jan;107(2):307-8]. Breast Cancer Res Treat. 2008;107(1):103-111.
    https://pubmed.ncbi.nlm.nih.gov/17333341/
  5. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases [published correction appears in BMJ. 2019 Jan 15;364:l162].
    https://pubmed.ncbi.nlm.nih.gov/30626577/
  6. Panay N, Ylikorkala O, Archer DF, Gut R, Lang E. Ultra-low-dose estradiol and norethisterone acetate: effective menopausal symptom relief. Climacteric. 2007;10(2):120-131.
    https://pubmed.ncbi.nlm.nih.gov/17453860/
  7. Stevenson JC, Durand G, Kahler E, Pertyński T. Oral ultra-low dose continuous combined hormone replacement therapy with 0.5 mg 17β-oestradiol and 2.5 mg dydrogesterone for the treatment of vasomotor symptoms: results from a double-blind, controlled study. Maturitas. 2010;67(3):227-232.
    https://pubmed.ncbi.nlm.nih.gov/20688442/
  8. Merki-Feld GS, Apter D, Bartfai G, et al. ESC expert statement on the effects on mood of the natural cycle and progestin-only contraceptives. Eur J Contracept Reprod Health Care. 2017;22:247–249.
    https://pubmed.ncbi.nlm.nih.gov/28728451/
  9. Shulman LP. A review of drospirenone for safety and tolerability and effects on endometrial safety and lipid parameters contrasted with medroxyprogesterone acetate, levonorgestrel, and micronized progesterone. J Womens Health (Larchmt). 2006;15(5):584-590.
    https://pubmed.ncbi.nlm.nih.gov/16796485/
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