Menopause

​Menopause: cessation of menstruation for 12 months without any medical cause; typically ages 45 and 55 (average 51)

Estrogen During Menopause

During perimenopause, the levels of estrogen are increased and there is greater drop than in younger women. Early in the transition, estrogen often becomes higher than normal, then falls more abruptly. ​Some women reach estradiol concentrations two to four times higher than those seen in younger women during certain cycles. The perimenopausal women (open circles) have consistently higher FSH concentrations throughout almost the entire cycle, often about 2–4 times those of the younger women. FSH remains elevated despite higher estrogen because declining inhibin B secretion from the aging ovary reduces negative feedback on the pituitary.
Santoro N, Brown JR, Adel T, Skurnick JH. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab. 1996 Apr;81(4):1495-501.

Early Menopause ​— Consider Hormonal Contraception

  • Consider menstrual cycle suppression during early perimenopause using continuous combined hormonal contraception (NuvaRing) but can use transdermal patch Xulane, Zafemy (generic Xulane), Twirla (lower dose), Gwyn Lo (lowest dose) (contain ethynyl estradiol):
— to suppress the higher average endogenous estradiol levels and fluctuating spikes of estradiol that characterise early perimenopause compared to premenopause
— to provide effective contraception
— to manage perimenstrual migraine
— to manage menstrual disorders
— to manage menopause symptoms
  • Healthy women with migraine without aura can use continuous combined hormonal contraceptives containing ethinylestradiol until age 50.

Continuous Combined Hormone Replacement (HRT) in Migraine

  • Continuous combined hormone replacement can be considered to manage vasomotor symptoms in women with migraine. Hormone replacement therapy increases risk of migraine. Transdermal estradiol (patch/gel/spray) is preferred where possible as it provides more stable levels compared to oral estradiol. Migraine aura does not contraindicate hormone replacement therapy. However, in view of the possibility of irregular bleeding from the natural cycle not being suppressed, cycle suppression may be more appropriate.
  • Women continuing HRT postmenopause should be advised that they are less likely to benefit from the gradual decline in migraine over the years that follow natural menopause seen in women who do not take HRT.
  • The optimal estrogen dose for women with migraine is the lowest dose that effectively controls vasomotor symptoms; high doses can be associated with increased headache and migraine. Start with transdermal estradiol 0.025 mg twice weekly. For those with more severe symptoms, start with 0.05 mg twice weekly.
  • Titrate no faster than every 4–8 weeks (e.g., 0.025 → 0.0375 → 0.05 mg/day) to the lowest dose controlling vasomotor symptoms; avoid large dose jumps that reproduce estrogen swings.

​Uterus Intact / Postmenopause ​— Methods to Add Progesterone

  • Continuous transdermal estradiol plus 52 mg levonorgestrel LNG-IUD (Mirena, Lileta) — protects uterine lining, local hormone reduces progestin-related side effects of mood changes, bloating and breast tenderness.
  • Continuous combined transdermal estradiol/progestogen patches — Climara Pro is preferred patch — may have mood swings, bloating or breast tenderness from the synthetic progestins in patches, so IUD or oral progesterone may be preferred
    • Climara Pro (estradiol/levonorgestrel) comes in only one strength, delivering 0.045 mg/day estradiol paired with the progestin levonorgestrel: 0.045/0.015 mg per day of estradiol/levonorgestrel, applied to the lower abdomen or upper quadrant of the buttock and replaced once weekly (every 7 days), with rotation of application sites. 
    • CombiPatch (estradiol/norethindrone acetate) comes in only two strengths, both delivering 0.05 mg/day estradiol paired with norethindrone acetate: 0.05/0.14 mg per day of estradiol/norethindrone acetate (9 cm²) and 0.05/0.25 mg per day of estradiol/norethindrone acetate (16 cm²), applied to the lower abdomen and replaced every 3–4 days (twice weekly). Should always use the 0.14 mg per day norethindrone acetate (lower dose).
  • Continuous transdermal estrogen (Climera, Vivelle-Dot, Alora) plus oral micronised bioidentical progesterone Prometrium 100 mg orally at bedtime daily

​Post Hysterectomy

  • ​Continuous transdermal (patch/gel/spray) 17β-estradiol (bioidentical) Climera, Vivelle-Dot, Alora

​Women with Migraine with Aura

​Women with migraine aura or who have other contraindications for ethinylestradiol and women over age 50 can use progestin + transdermal estradiol until age 55, by which time ovarian estradiol activity has declined sufficiently in most women to no longer trigger migraine.
  • 52 mg levonorgestrel (LNG) IUD ± transdermal estradiol
  • ​drospirenone 4 mg progestogen-only pill (Slynd) (omit 4 hormone free pills in pack) ± transdermal estradiol

Transdermal Estradiol Products for Menopausal Hormone Therapy — Bioidentical 17β-estradiol (E2)

Product Wear schedule Approved dose range Starting dose
Climara Once weekly 0.025–0.1 mg/day 0.025 mg/day
Vivelle-Dot Twice weekly 0.025–0.1 mg/day 0.0375 mg/day for VMS;
0.025 mg/day if osteoporosis prevention is the goal
Alora Twice weekly 0.025–0.1 mg/day 0.025–0.05 mg/day (label starting dose: 0.05 mg/day)
Minivelle Twice weekly 0.025–0.1 mg/day 0.025–0.0375 mg/day
Menostar Once weekly 0.014 mg/day Ultra-low dose; approved for osteoporosis prevention only
Estradiol gel
(e.g., Divigel)		 Daily, alternating thighs 0.25–1.25 g/day 0.25 g/day

Menopausal Vasomotor Symptoms

​​Antidepressants produced modest improvements in vasomotor symptoms.

Venlafaxine and low-dose oral estradiol equally effective in reducing hot flashes (50% vs 30% with placebo)
​
Reed SD, LaCroix AZ, Anderson GL, Ensrud KE, Caan B, Carpenter JS, Cohen L, Diem SJ, Freeman EW, Joffe H, Larson JC, McCurry SM, Mitchell CM, Newton KM, Sternfeld B, Guthrie KA. Lights on MsFLASH: a review of contributions. Menopause. 2020 Apr;27(4):473-484.

Veozah (fezolinetant) - NK3 Receptor Antagonist

Dose: 45 mg q day

​The neurokinin 3 (NK3) receptor antagonist fezolinetant (Veozah) is FDA-approved for treatment of moderate to severe VMS. Blocking neurokinin B activity restores hypothalamic thermoregulatory control, reducing VMS. In clinical trials in women with moderate to severe VMS associated with menopause, reductions in the frequency and severity of VMS were statistically significantly greater with fezolinetant than with placebo.19,20 Fezolinetant can cause abdominal pain, diarrhea, insomnia, back pain, hot flushes, and hepatic transaminase elevations. Fezolinetant is contraindicated for use with a CYP1A2 inhibitor.

LYNKUET® (elinzanetant) - NK3 & NK1 Receptor Antagonist

Dose: 60 mg q day

Transdermal Estrogen/Progestin Combinations

For menopausal vasomotor symptoms. Women with an intact uterus who take a systemic estrogen should also take a progestogen to reduce the risk of endometrial hyperplasia and adenocarcinoma. Progestin should not be used in women who have had uterus removed. Transdermal formulations are as effective as oral estrogens in reducing vasomotor symptoms and may be safer.
 
Climara Pro – Estradiol/levonorgestrel
Estradiol 0.045 mg + levonorgestrel 0.015 mg; per day; transdermal system.
Once per week.
 
CombiPatch – Estradiol/norethindrone
Estradiol 0.05 mg + norethindrone acetate 0.14 mg; per day; transdermal system.
Estradiol 0.05 mg + norethindrone acetate 0.25 mg; per day; transdermal system.
Twice per week.

Climara Pro and CombiPatch are in table below. Note that Climara Pro is once a week.

PROMETRIUM® (micronized progesterone for oral administration) Prevents Endometrial Hyperplasia