Alzheimer’s Reversal for Doctors: Sex Steroids

Alzheimer’s Disease for Doctors:
Sex Steroids

by Steven Wm. Fowkes

Top-down factors are components of the neuroendocrine system.  These factors play a supervisory role in regulating energy systems that are necessary for meeting the high energy demands of the brain.

For the prior blog on thyroid hormones, click here.

Sex Steroids

Sex steroids, like thyroid hormone, are very effective at raising metabolic rate with minimal side effects.  The precursors and metabolic pathways for steroid hormones are well known.  The rate-limiting step is cholesterol  conversion to pregnenolone.  And pregnenolone is a precursor for all sex steroids, mineralocorticoids and corticosteroids.  See the one-page Steroid Tree graphic if visual aids will help you follow these explanations.

Pregnenolone and Progesterone

Pregnenolone and progesterone are discussed together because they are both highly neuroprotective for human neural cell cultures.  No other steroids come close.  DHEA has some neuroprotective properties, but it takes ten time more to achieve the same cell viability for human neurons grown in cell culture.

There is a difference, however.  Although substantial pregnenolone is produced by the human body, it circulates only in trace amounts.  This is because pregnenolone has a strong likelihood of being immediately converted into DHEA and/or progesterone, both of which play huge roles in health in both men and women.

DHEA is the primary reserve-pool for sex hormones in humans.

Progesterone and testosterone play the same role in stimulating protein synthesis and energy metabolism.  Testosterone plays a minor role in women, whereas progesterone plays a vital role in both sexes.  The male-female sex difference in testosterone levels is ten to one for high testosterone women and a hundred to one in low-testosterone women.  But for progesterone, men and women have comparable levels.  So in men, progesterone and testosterone share the energy spotlight, whereas women rely almost exclusively on progesterone.

I now believe that salivary steroid tests are clinically superior to blood tests.  The blood is more of a storage compartment.  Sex steroids operate at the cellular and subcellular levels, which is where saliva comes from.

Two cautions.  Saliva testing is technically 1oo times more difficult technologically, so do not over-react to small changes in the numbers.  Also, small changes in blood hormone levels are associated with very large changes in salivary levels.  So don’t be overly concerned about normatively high numbers.


Testosterone increases protein synthesis and raises metabolic rate.  Despite what you may have heard, there are lots of testosterone receptors in the brain.  The myths about testosterone are rampant, have been covered elsewhere, and will not be covered here.

The key aspect of testosterone that needs assessment is aromatization into estradiol.  Inflammatory processes induce the aromatase enzyme, which converts testosterone into estradiol, and androstenedione into estrone.  The net loss of pro-metabolic effects from loss of testosterone, is aggravated by inhibition of metabolic rate by estrogens.  The primary indicator is low testosterone matched by elevated estradiol and estrone.  There is a secondary indicator of low serum tryptophan levels compared to other amino acids.   Clinically, a tertiary indicator is substantial increases in estradiol and estrone 3-5 weeks after initiation of testosterone replacement therapy.  For reliable assessment of this indicator, baseline estrogen measurements are needed.

In summary, the classical medical view that testosterone is the male hormone and estrogen and progesterone are the female hormones is wrong.  In both sexes, testoerone and progesterone are the energy-on switches and estrogens are the energy-off switches.  Although the testosterone switch in women may be minor regarding energy, for many women it is a major regulator of libido.  Although testosterone has a libido reputation for men, it only has this effect when correcting deficiencies.  Raising male testosterone above normal often has a libido-suppressing effect, promoting aggression, dominance and territoriality behaviors instead.

Estrogens: Estradiol, Estrone, Estriol

Although estradiol (E2) and estrone (E1) are similar in their suppression of protein synthesis and energy systems, estriol (E3) is different.  In fact, a high ratio of estriol to estrone plus estradiol (E3 / E1+E2) is protective regarding autoimmune disease risk.  Estradiol and estrone are also redox couples, being interconverted by the 17-beta-hydroxysteroid dehydrogenase enzyme.  Therefore, clinical assessment requires measuring both estradiol and estrone, in both men and women.

For the next blog on cortisol, click here.

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