An oral dose of 100 mg progesterone in a bioidentical hormone therapy combination that includes estradiol is sufficient to counteract potential estrogenic stimulation of the endometrium while improving moderate to severe vasomotor symptoms associated with menopause, according to an analysis of hormone levels in two studies.
Rogerio A. Lobo
Oral formulations of estradiol and progesterone in a single capsule have been challenging because of their differences in structure and solubility, Rogerio A. Lobo, MD, professor of obstetrics and gynecology and director of the reproductive endocrinology and infertility fellowship program at Columbia University Medical Center, and colleagues wrote in the study background. As of 2017, no combined estradiol/progesterone capsule had been approved by the FDA.
As Endocrine Today previously reported, the agency approved bioidentical estradiol and progesterone capsules (Bijuva, TherapeuticsMD) in October, following results from the phase 3 REPLENISH trial first presented at the Endocrine Society annual meeting in April 2017. The study demonstrated that a combination of 17beta-estradiol and progesterone appears to be safe and effective for reducing hot flash frequency and severity in menopausal women with a uterus.
“The primary objective of these analyses was to describe the levels of [progesterone] in the phase 3 REPLENISH trial, which were sufficient to counteract any potential estrogenic effects of 1 or 0.5 mg oral [estradiol] on the endometrial compartment when dosed continuously for 12 weeks,” the researchers wrote.
In REPLENISH, researchers evaluated the safety and efficacy of four doses of estradiol/progesterone against placebo in 1,835 postmenopausal women aged 40 to 65 years with an intact uterus and vasomotor symptoms, including a 1-mg/100-mg dose (n = 415) and a 0.5-mg/100-mg dose (n = 424). Mean age for the cohort was 55 years; mean BMI was 26.6 kg/m² and 67% were white. Baseline serum progesterone levels were below the level of quantification (0.05 ng/mL) for the majority of women. Mean baseline serum estradiol level was 6.1 pg/mL and mean serum estrone level was 23.3 pg/mL.
During the 12-month trial, mean levels of progesterone ranged from 0.39 ng/mL to 0.55 ng/mL for the 100-mg progesterone dose. Mean serum levels of estradiol ranged from 42.3 pg/mL to 45.6 pg/mL for the 1-mg estradiol dose and from 23 pg/mL to 27.4 pg/mL for the 0.5-mg estradiol dose. Researchers observed a dose response for estradiol and estrone levels with hormone levels remaining consistent during each treatment.
No cases of endometrial hyperplasia or endometrial cancer were observed among any of the groups.
In an analysis of data from a phase 1 study, researchers observed hormone level concentrations similar to those in REPLENISH, with progesterone levels averaging 0.53 ng/mL to 0.77 ng/mL with the 100-mg progesterone dose after 7 days of treatment at 8 to 12 hours after dosing.
“While these trough levels of [progesterone] are lower than luteal phase levels in ovulatory women, these values are significantly higher than the generally undetectable baseline levels of postmenopausal and sufficient to ensure endometrial protection,” the researchers wrote.
Additionally, the researchers noted that the combination of progesterone with estradiol in the same capsule did not inhibit the effects of estradiol on vasomotor symptom relief.
“Continuous dosing with 100 mg [progesterone] appears to be adequate to counteract the potential estrogenic effects of 0.5 mg or 1 mg [estradiol] on the endometrium,” the researchers wrote. “The evaluations reported here help to further our understanding of levels of [progesterone] required for endometrial protection when dosed in a continuous combined regimen with [estradiol] in postmenopausal hormone therapy.” – by Regina Schaffer
Disclosures: TherpeuticsMD sponsored the studies and supported the medical writing. Lobo reports he has received research grants from TherapeuticsMD and served as a consultant for Allergan, AMAG, JDS Therapeutics, Mithra, Pfizer, Teva and TherapeuticsMD. Please see the study for all other authors’ relevant financial disclosures.