Progesterone

Patricia Morse, Ph.D.
3/15/01

I decided to see whether I couldn't get some sense of the difficult progesterone question. Do we need it? What is it good for? It's an enormous and complicated topic, but, as usual, the direct concerns of women in surgical menopause have been given less attention, but for those of us in surgical menopause it may be essential to feeling good. It's such a big topic, I have to feel that this is a preliminary report from the trenches of the medical journals--but here goes.....

Progesterone is a hormone, which means that it's a messenger chemical that moves through the bloodstream, across a cell's membrane, and attaches to receptors in a cell's nucleus. Hormones are like keys searching for their locks. When they find the lock that they fit, they insert themselves and open the lock, starting one of many processes. Cells with these progesterone receptors are in the uterus, the central nervous system, the mammary glands in the breast, and the pituitary gland--as well as urinary and vaginal tissues.(9) It's most important role for the survival of the species is the fact it maintains pregnancy. Another word for pregnancy is gestation--pro-gestation = pro-gesterone. Progesterone levels are controlled by luteinizing hormone, which starts the chain of events that takes cholesterol and converts it pregnenolone, which in turn becomes progesterone. The end of progesterone release each month premenopause is the signal for menstruation.(9)

Surprisingly enough, progesterone can be made, not only in the ovary, but also in the adrenal glands and glial cells in the central nervous system (not to mention the placenta and even the testes, for thems as got 'em) (9). Some think that up to 60% of progesterone in healthy premenopausal women is made in the adrenal glands, (35) so many in surgical menopause may not need replacement once our adrenal glands get healthy.

The trouble comes in the Hormone Jungle (though of course it can strike others). We take extra estrogen and the ratio of progesterone to estrogen goes out of whack. As Dr. Joseph Collins says, "estrogen dominance" is the wrong term. It's progesterone too low in relation to estrogen that causes the problems--from the serious to just the unpleasant--though the estrogen itself may be low, progesterone is even lower (which is one reason why the too high/too low charts can be confusing). According to Collins, the normal premenopause ratio is somewhere between 20/1 and 120/1, Progesterone/Estrogen.

When the balance tips toward estrogen, it can contribute toward impaired liver function, it can decrease the action of vitamin B6, and it can increase aldosterone and prolactin.(16) Of course, it's not good if the progesterone levels get way too high in relation to estrogen either; then insulin resistance gets worse, depression and fatigue get worse, and libido drizzles away.(35)

But many of us already know all about progesterone/estrogen ratios when they go out of whack. That's what a lot of PMS is. Five to 10 days before menstruation, the ratio shifts so that estrogen goes up and progesterone goes down. We get irritable and aggressive because the estrogen boosts norepinephrine in the brain, and we retain salt and water because lower progesterone causes higher aldosterone. Emotional stress and high norepinephrine make progesterone levels even lower, and you can see why some women have it so hard. (3)

Just to remind ourselves, the symptoms of PMS are abdominal distension, breast tenderness, headaches, fatigue, dizziness, weight gain, fluid retention, joint pain, pelvic congestion, changes in appetite, poor immunity, diarrhea, constipation, herpes outbreaks, acne, insomnia, poor memory, grief, irritability, anger, anxiety, poor concentration, and confusion (3), not to mention edema (swelling) of the fingers and ankles (16) Estrogen is up and progesterone is down (17, 18, 19) and this list reads like a lot of the thickets and bramble patches in the Hormone Jungle. When the ratio is off, hypothyroid and elevated prolactin (breast soreness and even discharge from nipples) are common, and aldosterone goes up.(16)

What are the conditions that progesterone can help?

ALLERGIES

Allergies are often worse with low progesterone.(35)

ANXIETY

One of the most common tiger traps in the Hormone Jungle is the horrible anxiety that can come when the ratio is out of balance. Anxiety, nervousness, mood swings, and nervous tension and signs that estrogen is high and progesterone is low.(3) One way to address it is to increase levels of progesterone. But there are some natural ways to help your body do that. Vitamin B6 and magnesium (estrogen creates deficiencies) actually help with progesterone levels. Also known to help a lot is to increase fiber in your diet and to decrease saturated fat and refined carbohydrates (now where have we heard that before).(3) Progesterone itself soothes the nervous system. Progesterone can become chemicals in the brain that act just like Xanax and Valium to calm anxiety--though of course it's the other way around. Xanax and Valium act like progesterone!(35) Another pathway that affects mood is that high estrogen to progesterone ratios lower endorphins,(18) and endorphins normalize or improve mood.(16)

BONE LOSS

While the studies of progesterone alone don't show a real benefit, studies of estrogen in combination with bio-identical progesterone show an increase in building bone beyond estrogen's effect alone. So here's a clear case where estrogen and progesterone in balance enhance each other.(35) A test of mice showed that progesterone decreases bone turnover. Less bone was lost in the spine and in the femur when they were given progesterone, the higher in this case the better.(30)

BRAIN FOG

Progesterone can help clear the brain fog. Dr. Collins thinks that one of the signs of progesterone dropping too low is in fact a sense of confusion.(35) One preliminary study showed that postmenopausal women did better on some brain tests when they were on estrogen plus either progestin or progesterone than on estrogen alone.(4) Spatial cognition tests too showed that estrogen alone didn't have a positive effect. Though in this case, testosterone showed the most benefit.(28) Even more interesting, was that brain-damaged rats left in a water maze (aren't you glad you're not a lab rat?) did much better when given estradiol plus progesterone. They learned the maze and wandered less. Progesterone seems to protect learning and memory.(14) In another rat study, they mimicked the damage done by a stroke on the brain. Rats given progesterone after the stroke had significantly less damage and had more improvement in function afterward. In that case, progesterone protects the brain and nerves and may even help them regenerate.(13, 21) Progesterone can reduce cerebral edema (21) after an injury too.

EPILEPSY

Progesterone's calming influence extends to epilepsy too. It's anti-seizure effect is well known.(10) The problem is though that the metabolites play a big role, so that creams and the transvaginal may not have this good effect.

INSOMNIA

Progesterone can be sedating, bringing sleep on.(35) It also balances estrogen's effect on serotonin and norepinephrine, which both act to "overcaffeinate" us--causing us to be wired. It also helps too improve breathing patterns, even making sleep apnea better in some.(35). It's important to remember though that it's bio-identical progesterone that makes the biggest difference. There was a study that compared women on either Premarin and Provera (synthetic progestin) or Premarin and Prometrium (bio-identical progesterone). Women taking the Prometrium found they fell asleep more easily and stayed asleep for more of the night.(26) On the other hand, too much progesterone can be sedating and create fatigue, so you can have too much of a good thing. (35)

MIGRAINE

The picture isn't as clear here, but one beneficial effect may be the decrease in water retention. Some studies seem to show that the primary directly hormonal trigger of migraines is the withdrawal of estrogen. It's the changes in the sustained estrogen levels that appeared to trigger headaches the most often, including drops in progesterone levels.(29) Just our experience in the Jungle has shown that progesterone often helps with migraines that appear after taking estrogen.

PAIN

One of the signs that the progesterone estrogen ratio is out of balance is pain--muscle pains and joint inflammation.(35) Progesterone metabolites (the chemicals it breaks down into) are like barbiturates (well, barbiturates are like progesterone--which comes first the chicken or the egg after all?). They enter gamma aminobutyric acid receptors in the central nervous system and turn off the pain.(9) Inflammatory hyperalgesia is soothed by progesterone, which plugs into receptors in the spinal cord and brings relief.(5)

URINARY INCONTINENCE/VAGINAL PROBLEMS

Though a lot of studies need to be done, there's a steady drumbeat now of preliminary studies pointing to hormone replacement as an immediate treatment for urinary tract problems. They've been excited to find that there are both estrogen and progesterone receptors in both the urinary tract and the vagina. As one guy said, these seem to be target organs for estrogen and progesterone.(32) They have a more indirect effect too that makes them excited. After menopause, the pelvic floor gets weaker, leading to prolapse and incontinence. The muscle that controls the pelvic floor has its own estrogen and progesterone receptors. The connective tissues do too. So once again, having both estrogen and progesterone seems essential.(34)

WATER RETENTION

Weight gain, bloating, discomfort, breast tenderness, swelling of hands and ankles are all signs of high levels of aldosterone, which are caused by excess estrogen, magnesium deficiencies, and stress knocking out the good ratio.(16)

By balancing estrogen, does progesterone hurt some of estrogen's benefits?

CARDIOVASCULAR HEALTH

One reason that doctors can be adamant that women without uteruses should not be taking progesterone/progestins is that early studies using estrogen plus progestin showed that progestins decreased or even eliminated estrogen's good effects. However, now that more studies are being made with bio-identical progesterone, the picture is changing. The PEPI studies (you can find more on these in the heart articles here on the HJ) showed that bio-identical progesterone did not lower estrogen's benefit at all. There have been some recent studies that have shown it may even enhance estrogen's benefits when in balance with it. The abnormal growth of cardiac fibroblasts is connected to high blood pressure and heart attack. Estrogen alone did not slow the growth of fibroblasts but estradiol plus progesterone did.(24) Also a study of plaque in the arteries showed that, though estriol, low progesterone, and high progesterone all improved the plaque, it was progesterone that had the most effect.(27) It's been known to decrease high blood pressure.(35)

HOT FLASHES

It's just possible that progesterone might make hot flashes a bit worse, especially at first. It increases blood flow to the skin, increases the temperature of the skin, and increases metabolism, so you can sweat more.(35) It's not really a hot flash, but it does raise your thermostat.

LIBIDO/SEX

This is delicate balance in the Jungle. If the ratio is right, libido is improved and so it vaginal health. If progesterone is too high, then libido is decreased as depression is increased.(35) It can activate dopamine, and if the ratio is right, increase the pleasure from sex.(22) So the trick is getting the balance right.

WEIGHT

The subject of weight in the Hormone Jungle is vexed. Estrogen clearly has benefits for the digestive tract and insulin levels and fat distribution, but when it's high, it also creates water retention and weight gain, sometimes of many pounds.(33) Progesterone in balance can release the water weight. Estrogen can also cause a craving for sweets and carbs, which progesterone alone might not eliminate.(23) While some researchers feel that progesterone alone has no effect on body weight either way,(25) progesterone can upset estrogen's good effects on insulin. It may also, especially when progesterone is too high, stimulate the appetite.(35) After all, a pregnant woman is supposed to eat more. It's interesting that one way progesterone makes us feel better is through dopamine. And dopamine is the brain chemical that rewards us. In rats, they found that progesterone released more dopamine (feel good chemical), and a shot of estrogen changed it so the rats felt that food was a huge reward (more than sex even).(7, 8) So, getting the right balance is clearly necessary!

What are the kinds of progesterone replacement?

PROMETRIUM

Prometrium is the brand name of oral bio-identical progesterone that's micronized. "Micronized" means progesterone is reduced to particle sizes smaller than 10 micrometers (that's tiny). It allows it to pass through the intestinal wall. Suspension in oil and in gelatin capsules helps it absorb more.(9) It seems to produce quite variable amounts in women because it goes through the liver first. Progesterone levels peak within 2 to 3 hours of taking it and remain high for up to 12 hours. They return to baseline 24 hours after taken.(9) Over time, levels are more sustained and can take 84 hours to baseline.(9) This might be a clue if Prometrium starts to have side effects over time. The dose might be too high. Taking it with food resulted in increased peak levels.(9) In terms of benefits, it's like taking estrogen alone, and it makes no changes in liver enzyme levels (that's good) (9) Because it's oral, it goes through the liver first, where 90% of it is crunched up into other chemicals. As a result, these discard chemicals form unnaturally high levels in the blood stream. This is why Prometrium can cause dizziness and drowsiness, even if the ratio with estrogen may be ok.(1) It's still far better than the synthetic progestins--more health benefits and clear improvement in mood for the majority.(4) Some studies have shown that Prometrium has a much better effect on menopausal symptoms all around than the progestins.(6)

SKIN CREAM

Another form of micronized bio-identical progesterone comes in skin creams (if chemicals aren't made teeny tiny, they don't pass through the skin barrier). This is very controversial. Scientific studies can't get a consistent handle on how much progesterone is getting through. The skin barrier doesn't seem to allow for the administration of progesterone in the quantities necessary to protect against uterine cancer if one still has a uterus and one is taking estrogen.(1) It seems pretty clear, even in double-blind studies, that 1/4 tsp containing 20 mg of progesterone to the skin daily will improve menopausal symptoms by 83%--definitely better than a placebo. But they can't find a consistent gain in bone density (15) It seems as though the creams start to raise progesterone levels in about 60 minutes and reach peak levels at 1 to 4 hours after applying. Oral and vaginal progesterone reaches far higher doses, but a cream, especially a compounded cream with more strength and consistent amounts, can be enough to balance the progesterone/estrogen ratio. It does not seem to be strong enough to control the endometrium, which has consequences for sisters with endometriosis.(20) No one has figured out how it works, since it doesn't enter the bloodstream directly. Dr. Lee's theories haven't held up and they haven't found an alternative yet.

TRANSVAGINAL GEL

Transvaginal progesterone is a practical nonoral route that delivers high levels of progesterone direct to the uterus or the pelvic area. This might be a good choice for endometriosis control if other forms of progesterone throw off the balance. It has fewer side effects than other means.(1) Blood levels stay on a plateau, being much steadier. It probably doesn't help with anxiety and the other brain chemicals but it does enable a lower dose.(9)

PROGESTINS

Synthetic progestins are designed to resist enzymatic degradation and remain active. In other words, they go through the guy and the liver and are still there, which is both good and bad. They can have bad effects on the liver and can cause severe psychological side effects, especially a debilitating depression.(1) Women report significant increases in levels of tension/anxiety and depression on medroxyprogesterone acetate (Provera) so it's having the opposite effect of bio-identical progesterone in balancing estrogen.(4) Progestins don't copy the biologic activities of progesterone directly.(9) They sort of fill the same receptors, but then they go on and fill some of the androgen receptors too. Norethinodrone acetate (Aygestin) in particular has unintended consequences, since it's made from testosterone. Progestins work against estrogen's cardiovascular benefits and can bringon glucose intolerance.(9) Basically, the side effects are strong, they don't always bring balance to the progesterone/estrogen ratio, and the doctors who say, no progestins, are probably right.

Are there other ways to affect the progesterone/estrogen ratio?

BORON

High levels of boron are a bad thing for the progesterone/estrogen ratio. It affects the absorption of calcium, magnesium, and phosphorus, but worse it increases estrogen production (and even those of us in the Hormone Jungle are producing some estrogen). So don't add boron.(35)

DIET

It's not going to be news that eating more vegetables, fruit, and whole grains and less saturated fat, simple carbohydrates, and sugar is going to improve your sense of balance. Potassium is important for water retention and present in this diet. Yogurt too will help--it helps create healthy intestines, so the hormones can be processed well.

STRESS

Stress has a bad effect on the progesterone/estrogen ratio, just as it has a bad effect on everything else. In particular, the adrenal glands under stress can grab progesterone out of the blood stream and turn it into cortisol, the damaging stress hormone.(35) Stress increases levels of aldosterone, which increases fluid retention while lowering progestesrone. And stress lowers the feel good endorphins that progesterone can increase.(16)

MAGNESIUM

As usual in the Jungle it plays a large role in negotiating hormonal balance and estrogen uses it up in its processing. So, supplements of it will help too.

VITAMIN B6

Progesterone out of balance can lower vitamin B6 levels even more than estrogen alone. B vitamins help maintain liver health too. The liver needs B vitamins to break down estrogen. If it can't break down estrogen, the levels of estrogen increase.(16) With B vitamins low, prolactin increases, leading to more breast tenderness. Vitamin B6 and zinc lower prolactin. So supplements with a B vitamin complex will help with the ratios and the sense of balance.

REFERENCES

1. Warren, M. P., and S. Shantha. 1999. Uses of progesterone in clinical practice. International Journal of Fertility and Women's Medicine. 44:96-103.

2. Strijks, E., et al. 1999. Effects of female sex steroids on Parkinson's disease in postmenopausal women. Clinical Neuropharmacology 22:93-97.

3. Caldecott, T. 2000. Natural treatments for PMS symptoms. Rising Women Archives. http://www.risingwomen.com/Caldecott.htm.

4. Harbour, K. E. 1999. the use of medroxyprogesterone acetate versus micronized progesterone in postmenopausal women: neuropsychological and psychological implications. Dissertation Abstracts, sect. B. 60(5-B):2342.

5. Ren, K. et al. 2000. Progesterone attenuates persistent inflammatory hyperalgesia in female rats: involvement of spinal NMDA receptor mechanisms. Brain Research 865:272-277.

6. Fitzpatrick. L. A., et al. 2000. Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey. Journal of Womens Health and Gender-Based Medicine 9:381-387.

7. Rehavi, M., et al. 2000. Suppression of serum gonadal steroids in rats by chronic treatment with dopamine and serotonin reuptake inhibitors. European Neuropsychopharmacology 10:145-150.

8. Bless, E. P. 1998. Effects of ovarian hormones on the mesolimbic dopamine system in female rats. Dissertation Abstracts International, sect. B. 58:5691.

9. Fitzpatrick, L. A., and A. Good. 1999. Micronized progesterone: clinical indicatiosn and comparison with current treatments [review of 74 studies]. Fertility and Sterility 72:389-397.

10. Frye, C. A., and T. I. Scalise. 2000. Anti-seizure effects of progesterone and 3alpha, 5 alpha-THP in kainic acid and perforant pathway models of epilepsy. Psychoneuroendocrinology 25:407-420.

11. Deligdisch, L. 2000. Hormonal pathologty of the endometrium. Modern Pathology 13:285-294.

12. Yang, Q., and G. Owusu-Ababio. 2000. Biodegradable progesterone microsphere delivery system for osteoporosis therapy. Drug Development and Industrial Pharmacy 26:61-70.

13. Chen, J., et al. 1999. Neuroprotective effects of progesterone after transient middle cerebral artery occlusion in rat. Journal of Neurological Sciences 171:24-30.

14. Vongher, I. M., and C. A. Frye. 1999. Progesterone in conjunction with estradiol has neuroprotective effects in an animal model of neurodegeneration. Pharmacology, Biochemistry, and Behavior 64:777-785.

15. Leonetti, H. B., et al. 1999. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstetrics and Gynecology 94:225-228.

16. A comprehensive evaluation of premenstrual syndrome. 2000. Clinical Research Bulletin vol. 1, no. 14. http://www.vitaminusa.com/arherevofpms.htm.

17. Barnhardt, K. T., et al. 1995. A clinician's guide to the premenstrual syndrome. Medical Clinician of North America 79:1457-1472.

18. Facchinetti, F. et al. 1983. Estradiol/progesterone imbalance and the premenstural syndrome. Lancet 2:13-2.

19. Munday, M. R., et al. 1981. Correlations between progesterone, estradiol, and aldosterone levels in the premenstrual syndrome. Clinical Endocrinology 14:1-9.

20. O'Leary, P., et al. 2000. Salivary but not serum or urinary levels of progesterone are elevated after topical application of progestertone cream to pre- and postmenopausal women. Clinical Endocrinology 53:615-620.

21. Asbury, E. et al. 1998. Progesterone facilitates the acquisition of avoidance learning and protects against subcortical neuronal death following prefrontal cortex ablation in the rat. Behavioural Brain Research 97:99-106.

22. Mani, S. K., et al. 2000. Requirements for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice. Science 287:1053-1056.

23. Michener, W. et al. 1999. The role of low progsterone and tension as triggers of perimenstrual chocolate and sweets craving: some negative experimental evidence. Physiology and Behavior 67:417-420.

24. Dubey, R. K., et al. 1998. 17Beta-estradiol, its metabolites, and progesterone inhibit cardiac fibroblast growth. Hypertension 31:522-528.

25. Biegon, A. et al. 1983. Behavioral and neuroendocrine effects of long-term progesterone treatment in the rat. Neuroendocrinology 37:332-335.

26. Montplaisir, J., et al. 2001. Sleep in menopause: differential effects of two forms of hormone replacement therapy. Menopause 8:10-16.

27. Houser, S.L., et al. 2000. Serum lipids and arterial plaque load are altered independently with high-dose progesterone in hypercholesterolemic male rabbits. Cardiovascular Pathology 9:317-322.

28. Hausmann, M. et al. 2000. Sex hormones affect spatial abilities during the menstrual cycle. Behavioral Neuroscience 114:1245-1250.

29. Siberstein, S.D. 2000. Sex hormones and headache. Revue Neurologie (Paris). 4(suppl.):4S30-4S41.

30. Tang, O.S., et al. 2000. Further evaluation on long-term depot-medroxyprogesterone acetate use and bone mineral density: a longitudinal cohort study. Contraception 62:161-164.

31. Krejza, J., et al. 2001. Effect of endogenous estrogen on blood flow through carotid arteries. Stroke 32:30-36.

32. Blakeman, P.J., et al. 2000. Oestrogen and progesterone receptor expression in teh female lower urinary tract, with reference to oestrogen status. British Journal of Urology 86:32-38.

33. Gruber, D. M., et al. 1997. [The significance of progesterone and gestagens in climacteric.] Zentralblat Gynakologie 119(suppl.)2:34-38.

34. Smith, P. et al. 1993. Localization of steroid hormone receptors in the pelvic muscles. European Journal of Obstetrics, Gynecology, and Reproductive Biology 50:83-85.

35. Collins, J. 2000. What's your menopause type? Prima Health, Roseville, Calif.