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Progestogen Intolerance and Compliance with HRT


Feb 11, 2013
This UK study relates to progestogens in the first place, but constant references are made to progesterone, which is by the authors' admission a better option:

Negative mood effects

Progesterone receptors are found in the caudate, cerebellum, cortex, habenula, hippocampus, hypothalamus, olfactory lobe, lamina terminalis and area postrema (Maggi and Perez, 1985). Limbic system functions, which subserve emotion and behaviour, can therefore be influenced by circulating reproductive steroids such as progesterone and progestogens. There is evidence that progesterone and progesterone metabolites affect a number of central nervous system (CNS) transmitter systems to bring about mood changes, and these effects can be extrapolated to the progestogens in HRT (Backstrom et al., 1996).

Progesterone metabolites and the GABAA receptor The γ-aminobutyric acid A (GABAA) receptor usually has anti-anxiolytic properties. It has been suggested that pregnenolone sulphate, a progesterone metabolite, may have antagonistic properties leading to inhibition of the GABAA receptor, thus producing negative mood effects.

Effect of progesterone on monoamine turnover and metabolism

Progesterone and progestogens have been shown to increase the metabolism and turnover of monamines in the rat brain. Also, platelet monamine oxidase activity has been shown to decrease in the luteal phase. These effects could theoretically produce negative mood changes.

Serotonin system

Studies have shown that the serotonin uptake and content of platelets is significantly lower in the premenstrual phase in patients diagnosed with premenstrual syndrome (PMS) compared to controls. There is also evidence for the beneficial effects of serotonin re-uptake inhibitors on PMS symptoms. It is therefore possible that symptoms related to the progestogenic component of HRT are in part due to actions on the serotonin system.

Nonandrogenic progestogens and progesterone have the best physical effects, although they are not devoid of psychological effects. Anxieties about adverse lipid changes, increased vascular resistance and increased insulin resistance may be an issue in the patient who has either pre-existing cardiovascular disease or who develops cardiovascular disease whilst receiving HRT. In these patients it would be wise to use at the outset, or change to, progesterone itself or a less androgenic type of progestogen. Therefore, these progestogens are currently being incorporated into HRT regimens wherever possible in preference to those that are more androgenic.


Oral micronized progesterone has been developed to overcome absorption problems that meant in the past it had to be given by injection, vaginally or rectally. Unlike many oral progestogens, side effects are uncommon with progesterone administration. Dalton (1977), using low-dose progesterone for the treatment of PMS, claims not to have detected any adverse effects in 40 women treated over 10 years for PMS. Oral micronized progesterone, 300 mg per day for 12 days each month, or progesterone suppositories, 25 mg twice daily for 12 days, can be used as progestogenic opposition. Recently, interest has been generated in exploring the potential of natural progesterone cream derived from plant sources, including wild yam, where it is found in its precursor form, diosgenin. Nutritionists and some doctors claim that it is sufficient in itself to provide relief of short- and long-term menopausal problems, including reversal of osteoporosis. Unfortunately, the bone data have been collected only from a few uncontrolled cases. This cream certainly does appear to have minimal adverse effects, and anecdotally some patients do seem to derive benefits of increased energy, libido and improved skin. However, prospective, randomized, placebo-controlled studies are necessary to confirm the claims of its benefits; these have not yet been performed. It would also be interesting to see whether it could used as progestogenic opposition for oestrogen therapy.

My observation would be that Dalton wrote the book on PMS and knew very well how to tell an estrogen-dominant woman from a progesterone-dominant woman. If she chose to treat those women, they must have indeed needed that progesterone, there's no question. So, no side effects. Therefore, hers may have hardly been the kind of scientific study that demonstrates the safety of progesterone supplementation...

N. Panay and J. Studd said:
Pregnenolone sulphate appears to have an action at the N-methyl-D-aspartate (NMDA) receptor, which is part of the excitatory CNS, but the role of the receptor in the hormonal effects on mood is still unclear. The times in a woman’s life when oestrogen concentrations are low, i.e. postpartum and in the perimenopause, or when progesterone concentrations are high, i.e. premenstrually, is when the greatest excess of depression occurs. There are indications that it is the high luteal phase progesterone concentrations which exacerbate PMS symptoms such as depression and mood swings. This is supported by the fact that abolition of ovulation with GnRH analogues or percutaneous oestrogens alleviates symptoms.

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