Progesterone Therapy for Perimenopause & Menopause
HRT encompasses several drug classes, including oestrogens (detailed blog post here), progestogens (detailed blog here), oestrogen plus progestogen combinations, synthetic steroids (e.g. tibolone), and selective oestrogen receptor modulators (e.g. raloxifene, bazedoxifene, ospemifene).
In this post I want to dive into the progesterone component of HRT.
Role of progestogens
Oestrogen is the main or “lead” component of HRT that relieves the vasomotor and urogenital symptoms of menopause and protects against osteoporosis. The medical opinion is that women with a uterus require a progestogen to prevent endometrial hyperplasia and the risk of endometrial cancer associated with the use of unopposed oestrogen. In my opinion, all women on oestogen therapy , irrespective of if they possess a uterus, should be prescribed progesterone. After all, progesterone receptors are found not exclusively to the uterus, but are found in the breast, ovary, brain, bone, musculoskeletal, cardiovascular and immune systems as well as in all cells and tissues of the body. As a result progesterone plays an integral role in the normal physiology of the brain, cardiovascular, musculoskeletal, nervous and immune systems.
Delivery methods
Progestogens for use in HRT regimes are available as single agents for accompanying use with oestrogen or in fixed combinations with estradiol in the form of tablets or patches. As a reminder, Progestogens is a collective term that encompasses natural progesterone, and a range of synthetic drugs termed progestins (read detail post here).
Progesterone that is manufactured from a vegetable base( soya or yam) as a medicine is identical to the progesterone made by ovaries and adrenals, and therefore termed "bio & body-identical," possessing the same whole body actions as our a woman’s own hormone. As such for most women, bio & body-identical progesterone is the preferred form used in HRT pairing.
In other words, progesterone is needed for body -wide health, not just reproduction. Let’s now review progesterones actions …..
Actions of endogenously produced & bio-indentical progesterone :-
Anti oestrogenic (counter balances oestrogens proliferic action)
Anti androgenic (prevents androgens like testosterone and dihydrotestosterone from mediating their biological effects in the body, which in women presents as acne, hair loss & hirsutism)
Antimineralcorticoid ( induce a transient reduction in (aldosterone-induced) water retention
A neurosteroid; progesterone is metabolized( broken down) into allopregnanolone and pregnanolone, which potent activators of the GABAA receptor delivering anxiolytic( calm anxiety), anticonvulsant, sedative, hypnotic, euphoriant, and muscle relaxant properties.
Routes of delivery include:
Orally > as micronised progesterone capsule( utrogestan), micronised progesterone combined with body identical estradiol capsule (Bijuve), as the progestins Dydrogesterone, Medroxyprogesterone acetate, Norethisterone and Drospirenone in solo tablets of combined with body identical estradiol ( see chart1)
Vaginal > as vaginal micronised progesterone
Transdermal > as micronised progesterone in compounded creams or as progestins in combination patches ( see chart1)
Intrauterine > as a progestin( levonorgestrel) IUD, contains 52mg, slowly releases continuous low dose into uterus
Progestagens as either
|
Brands | Delivery |
Hormonal Activity AE- antioestrogenic AND- androgenic AA-antiandrogenic AM-antimineralcorticoid GLU=glucocorticoid EST- oestrogenic |
|---|---|---|---|
Progesterone + estradiol hemihydrate |
Bijuve | Bijuve | AE|AA|AM |
| Levonorgestrel | Mirena Combined patches FemSeven conti |
IUD Patch |
AE|AND| |
| Norethisterone | Combined patches Evorel conti & Sequi Combined tablets Kliovance Kliofem Novofem Trisequens Estelle Duet |
Patch Tablets Tablets Tablets Tablets |
AE|EST|EST| |
| Dydrogesterone | Femeston range Duphaston |
Tablets Tablets |
AE| weak AM |
| Medroxyprogesterone acetate | Combined tablets Indivina Solo Provera |
Tablets Tablets |
AE| weak AND|GLU |
| Drospirenone |
Combined tablets Angeliq |
AE|AA | |
Selecting a progestogen
As tolerability to progestogens varies considerably among women, treatment must be individualized. Treatment should begin with a progestogen that has the lowest risk profile regarding breast cancer and cardiovascular effects, while addressing her specific needs and risk factors. Numerous opinion leaders such as Dr. Jerilynn C. Prior, guideline groups, and menopause societies recommend as the gold standard choice micronized progesterone or secondly dydrogesterone to estrogen therapy as the associated cardiovascular, thromboembolic, and breast cancer risks are lower with these molecules compared with other progestogens. When we appreciate the multiple actions of progesterone, we can see why this is the preferential choice.
So if micronised progesterone is SO wonderful, why do progestins even exist?
When progesterone was first discovered and began being used as an oral medicine in the 1920s, the stomach and intestines broke it into molecules, rendering them inactive. In a quest to find a medicine to protect the uterus, dozens of chemicals were created; as progesterone & testosterone derivatives (see Progesterone & Progestin unpacked post here) as the base to create a molecule with progesterone's two key uterine actions. These chemicals were widely marketed and came to be used with oestrogen as part of HRT. It wasn't until 1980 that French scientists discovered that micronized progesterone (ground into a powder) and suspending in oil would allow it to be active by mouth allowing for a steady and even absorption. This is utrogestan.
The Benefits of Micronized Progesterone as Utrogestan
Micronized Progesterone, is still subject to first pass metabolism (via the stomach and intestine), however the metabolites produced are active compounds, such as allopregnanolone which crosses the blood brain barrier, binds to GABA receptors and thereby elicits calm and promotes sleep.
The combination of micronized progesterone and its suspension in oil enhances absorption from the intestines and improves its bioavailability body-wide.
Progesterone, as a steroid hormone, synthesized from cholesterol is lipophilic( fat-loving), this matters because when progesterone is applied as a cream to the thigh, breast, arm, buttock the hormone is immediately taken up by that adipose tissue to where in the body it's been applied. This is beneficial when applied to the breast for example to alleviate breast pain , but topical application does not reach and protect the endometrium nor will it grow through first pass metabolism and form allopregnanolone.
Besides progesterone‘s uterine actions what else does progesterone do?
1. Treats Hot Flushes/and Night Sweats
CeMCOR scientists, funded by private donations conducted a highly successful randomized, placebo-controlled trial of progesterone versus placebo [1]. In addition, progesterone for VMS treatment shows no withdrawal-related increased VMS when it is stopped, in contrast to oestrogen treatment alone which often causes a rebound increase in hot flushes [2].
2. Improves Sleep
Progesterone crosses the blood-brain barrier, which progestins do not, and has known interactions with brain neurotransmitters[3]. The result of progesterone's brain actions is an ability to fall asleep faster, less disturbed deep sleep and overall increased total sleep time
3. Enhances Thyroid Functionality
4. Enhances Positive Bone Balance Through Increasing Bone Formation
Progesterone, acting through its receptor on the osteoblast (bone-forming cell), stimulates new bone formation. It does this in two ways—by increasing numbers of osteoblasts and by increasing the ability of osteoblasts to lay down the protein "foundation" of bone called osteoid
References:
Hitchcock CL, Prior JC: Oral Micronized Progesterone for Vasomotor Symptoms in Healthy Postmenopausal Women—-a placebo-controlled randomized trial. Menopause 2012, 19: 886-893.
Prior JC, Hitchcock CL: Progesterone for hot flush and night sweat treatment - effectiveness for severe vasomotor symptoms and lack of withdrawal rebound. Gynecol Endocrinol 2012, 28 Suppl 2: 7-11.