Dr. CY Lee, MBBS, MAFP, FRACGP, IHS
What does the evidence say?
Often questions are asked which form of progesterone better, oral or transdermal. Why does one recommend progesterone? What are the basis and effects of the form of progesterone used?
Progesterone is a naturally occurring steroid hormone. Its half-life is only 5 minutes and it has a very poor bioavailability orally.
Progesterone causes the secretory transformation of the endometrium from the estrogen-induced proliferative phase during the second half of the menstrual cycle. Progesterone also exerts its effect on the breasts and the CNS.
Progesterone is primarily being used to manage following conditions:
- To regulate the menstrual
- Treat dysfunctional uterine bleeding.
- Prevention endometrial cancer or hyperplasia in unopposed estrogen stimulation. Progesterone reduces estrogen receptors in endometrial glands. It also regulates mitosis in fully differentiated endometrial cells.
- It is also used as a form of contraception.
- It has been used to treat dysmenorrhea and premenstrual syndrome.
- It is also has been used to prevent, control and possibly reverse ovarian cysts and fibroadenomas of the breast. In addition, further enlargement of fibroids and formation of new fibroids may be controlled but reducing the size of existing fibroids needs long term use. Furthermore, menorrhagia secondary to fibroids can be controlled thus avoiding surgery in most cases.
Synthetic analogues of progesterone called “progestins” are associated with much side effects like-fluid retention, reduction on HDL, headache, mood disturbances and androgenic effects.
But natural progestogen that is primarily obtained from plant source has not been shown to affect the mood, reduction HDL or adversely affect pregnancy outcome.
Since natural progesterone has been associated with poor bioavailability, a micronized form has been developed to minimize this issue. With micronizing, the half-life of progesterone is increased and its destruction in the gastro intestinal tract reduced.
Various clinical trials have established that the sequential oral use of 200 mg progesterone daily offers reliable protection against undesirable effects of oestrogen on the endometrium, i.e. it prevents endometrial hyperplasia.
The USA PEPI study is a landmark trial. It showed the evidence of the endometrial safety of hormone replacement therapy (HRT). 875women were treated for three years with various HRT regimes, including one arm with oral administration of 200 mg micronized progesterone daily on 12 days of every month as an addition to a standard dose of 0.625 mg conjugated equine oestrogens (CEE) daily. The incidence of endometrial hyperplasia was no difference as that found under placebo (1–4% of the women), whereas the 3-year use of oestrogen alone led to such hyperplasia in 62% of the women.
The KEEPS trial included 727 women who were newly menopausal. The trial tested 2 different types of oestrogen compared with placebo: a low-dose oral conjugated oestrogen at a dose of 0.45 mg/day, and a transdermal estradiol patch at a dose of 50 µg/day. Both [forms of oestrogen were taken] with cyclic micronized progesterone for 12 days per month.
There was a substantial reduction in menopausal symptoms (hot flashes, night sweats) and also some improvement in bone mineral density [were seen in the active treatment groups]. Systolic blood pressure was not increased and there was the neutral effect on cognitive function.
Natural progesterone and synthetic progestins do have different adverse effects profile. Fournier, et al studied the different HRTs and breast cancer risk. His study involved 80,377 postmenopausal women up to 12 years of follow-up. His result showed that breast cancer risk is associated with the use of oestrogen alone, and in those who use oestrogen with other synthetic progestins. However, oestrogen in combination with micronized progesterone or dydrogesterone is not associated with an increased risk of breast cancer.
The transformation from the reproductive to the post-reproductive phase in a woman’s life lasts a few years. It is characterised by cycle disturbances ranging from dysfunctional bleeding to secondary amenorrhoea, which can be treated with oral micronized progesterone evidently. How about transdermal form?
The transdermal use of progesterone.
When progesterone is used transdermally, there is a reservation with regards to the inadequate therapeutic serum level. These raised doubts about corresponding systemic effects. In the majority of the studies, progesterone creams used were unable to achieve peak serum level of more than 1ng/ml. The normal reference range quoted during luteal phase is usually 5 to 20 ng/mL. In some studies, however; the salivary levels of progesterone did increase significantly especially in postmenopausal women and fingertip capillary blood but without a concurrent dramatic increase in the serum level.
Most of the progesterone used in menopausal women is to protect overstimulation of the endometrium by the concurrent use of oestrogen. But the transdermal use of progesterone may not be able to provide sufficient blood and tissues level to protect the endometrium. Arvind Vashisht and associates did a study on the effects on the endometrium for women using a novel combination of transdermal oestradiol and natural progesterone cream as part of an HRT. Women at least 2 years of post menopausal were recruited and they applied 40 mg natural transdermal progesterone cream and 1mg transdermal oestradiol daily. They have concluded that the dose of natural progesterone cream in their study was insufficient to fully attenuate the mitogenic effect of oestrogen on the endometrium.
Australian researchers led by Wren also showed no progestogenic effect of the sequential addition of transdermal progesterone 16–64 mg daily given for 14days per 28-day cycle to continuous use of 100 microgram estradiol daily; about 90% of the women showed a proliferating endometrium after three cycles.
So far there are conflicting results with regards to the effect of transdermal progesterone alone in reducing vasomotor symptoms.
Bernster and co-workers sought to evaluate the effect of progesterone cream on the climacteric symptoms in post-menopausal women. 223 healthy postmenopausal women, aged between 40 and 60 years and complaining of severe menopausal symptoms was recruited. They were randomly allocated to progesterone cream 60, 40, 20, 5 mg or placebo, to be applied daily continuously for six months. There were no statistically significant differences between any of the treatment groups and placebo for any of the components of the Greene Climacteric Score. They concluded that Progesterone cream was no more effective than placebo for relief of menopausal symptoms.
Whelan AM and co-workers did a systematic review of the effect of transdermal progesterone on climacteric symptoms. 3 RCTs were identified. 2 RCTs failed to see the beneficial effect. Only 1 RCT which used specific compounded progesterone for the trial showed a beneficial effect. The author concluded that available evidence from RCTs does not support the efficacy of bio identical progesterone cream for the management of menopause-related vasomotor symptoms.
Wren BD and co-workers did an RCT comparing the effect of a transdermal cream containing progesterone (32 mg daily) with a placebo cream over a period of 12 weeks. There was no detectable change in vasomotor symptoms, mood characteristics, or sexual feelings, nor was there any change in blood lipid levels or in bone metabolic markers, despite a slight elevation of blood progesterone levels.
Studies conducted to date with progesterone cream have no consistent effects on bone metabolism, lipids, inflammatory and clotting parameters or on the progression of atherosclerosis. Bernster B and co-workers ivestigated 131 post-menopausal women between 50 and 75 years, each with at least one atherosclerotic plaque detected by ultrasound was divided into groups and instructed to use 40 (2 × 20) mg progesterone as cream or placebo for 3 years. No major differences between progesterone cream and placebo were noted. The authors concluded that in the dosage used, the progesterone cream has no influence on the course of atherosclerosis or the preservation of bone.