Progesterone intolerance and 5AR: the biphasic nature of Allopregnanolone
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https://ahha.org/xresearch-articles/townsend-letter-the-clinical-importance-of-5alpha-reductase/
Estrogen dominance is a common reason women cannot tolerate progesterone. As we know from Peat and @Haidut, this can show up even in women with low blood estradiol levels. In menopause, estrogenic uptake and activity is even higher in tissues. However, 5-AR activity may be high in these women whose side effects are not explainable by high blood estrogen.
The hypothesis of the paper is that 5α-R excess causes PMDD; postpartum depression; catamenial seizures; menstrual migraine and alopecia, acne and hirsutism. Treating with a 5-ar inhibitor (Saw Palmetto here), they claim, is desirable here as long as you are not having a baby (as 5-AR inhibition could make the male offspring a hermaphrodite).
*“The informed reader is excused for resisting the statement: “Too much progesterone causes PMDD/ PMS when added to excessive 5α-R.” Many practitioners understand that PMDD/ PMS is caused by “estrogen dominance,” meaning too little progesterone.[lxxxvi] After all, Dalton proved women with PMS respond to added progesterone [lxxxvii] – but relevant for this paper, she later stated doses had to be of pharmacological-strength (supra-physiological) and that testing blood progesterone revealed nothing significant.[lxxxviii] [lxxxix]
Dalton’s methods are still applied. At (Integrative) meetings, Practitioners state some patients require 400 mg (or even more) oral progesterone daily to relieve their PMDD/ PMS symptoms. Blood tests show the resulting progesterone levels are consistent with advanced pregnancy… the term “Progesterone Resistance” is applied. These observations are valid and it seems 5α-R excess and ALLO can explain this “resistance,”*
Case 1 reacted badly to progesterone (Prometrium) and gained weight. This is due to high 5-AR levels, which converted it into allopregnanolone. High 5-AR women cannot tolerate decent doses of progesterone without neurological symptoms.
The 5-AR acts undesirably in women by turning cyclically turning high luteal progesterone into allopregnanolone, and turning DHEA into high levels of androsterone. This shows in blood.
ALLO has a bimodal effect. Too little and too much can both cause neurological symptoms. ALLO affects signaling of brain and spinal cord.”very high ALLO may be analgesic (as in pregnancy) but luteal phase ALLO levels can be associated with heightened sensitivity to pain.”
Low Allo in men is correlated to anxiety and pain sensitivity: “among male veterans who served in war zones, low ALLO blood levels are significantly associated with low-back and chest pain”
“Researchers able to measure ALLO find women with PMDD have higher ALLO compared to progesterone (ALLO/progesterone ratio)53 and on taking oral progesterone, these women produce the mostALLO of anyone.[liv] Their blood levels of ALLO consistently reflect those of progesterone: Lowest in follicular and highest in luteal (when symptoms emerge) and then low again at the onset of menses (when symptoms remit).[lv] [lvi] Furthermore, symptoms are absent when progesterone fails to rise during anovulatory cycles[lvii] [lviii] and taking progesterone can worsen their symptoms.53”
“In a well-designed study, investigators found serum ALLO values between 1.5 and 2.0 nmol/L are associated with significantly negative mood… but women’s mood is good when concentrations are either lower or higher(Figure 4) – a bi-modal effect.[xc] The researchers had given menopausal women various doses of progesterone orally and so-doing, also found the progesterone blood levels producing the “dysphoric” amounts of ALLO are those of normal endogenous luteal phase. Either lower or significantly greater blood levels were better tolerated. Upholding Dalton, the fact is: The ill-effects of “too much” progesterone producing “too much” ALLO can be overcome by giving more progesterone (Figure 4).
The hypothesis given is that when progesterone exceeds the reaction capacity of 5-AR, it starts to increase beyond the levels of ALLO.
In case 1 Test was lower than DHT whereas it should be double the DHT level in women. Test was very low not because it wasn’t a problem, but because it was getting reduced. Both were still low (normal DHT is 4-22 and hers was only 3.5 ng/dL). But DHT stimulates androgen receptors 10x more than test so it is a problem for women. Although her DHT is so low, in the context of her general hormonal deficiency it showed a problem.
5-ar “deficiency” causes no problems in women. They will have very little body hair and freedom from acne.
In case 4, Saw Palmetto at 160mg/day alleviated migraine headaches.
Case 3, as months progressed, saw less cramps, lighter and shorter flow, cycle normalized to 28 days, and lower breast tenderness, and reduced odor (apocrine axillary secretions of androsterone). Thicker hair in front.