Progesterone and the Nervous System

Presented at the Anti-Aging Medicine World Congress & Medispa, Monaco 2010

Progesterone is produced in the ovaries, the Leydig cells of the testicles, and in the adrenal glands. Many people don’t realize that progesterone is also made in the glial cells of the nervous system, both in the brain and in the Schwann cells of the peripheral nervous system.

Progesterone receptors are found in the uterus, the breasts, the ovaries, the prostate, the liver, in sperm cells, the epithelial cells of the eye, in the brain, and in the peripheral nervous system.

There are two isoforms of progesterone receptors: PR-A and PR-B. PR-B is a “full length receptor,” whereas PR-A is missing 164 amino acids compared to PR-B. The ratio of PR-A and PR-B levels determine type and extent of the progesterone effect. PR-A is responsible for progesterone-dependent reproduction and PR-B for normal differentiating effects. PR-B is more active than PR-A, and is cell-specific. PR-A suppresses transcription activities of other steroid hormone receptors, including estrogen receptor alpha (ERα) and PR-B.

There are also two isoforms of 3 beta-hydroxysteroid dehydrogenase, an enzyme that catalyzes the synthesis of progesterone from pregnenolone: Type I in the placenta and the skin, Type II in the adrenal glands, the ovaries and the testicles.

Research has shown that gonadotropin (e.g. FSH and LH) suppression is mediated by the progesterone receptor. Progesterone reduces LH, FSH and testosterone in women and men. It reduces pulsatile frequency of LH, but has little affinity for the androgen receptor.

The anti-anxiety effects of oral progesterone in men were demonstrated in 1987 by De Lignieres. Progesterone versus placebo was administered in 38 men with anxiety symptoms in a double-blind crossover study. Hamilton’s Anxiety-Scale was significantly reduced 4 hours after progesterone administration and remained lower at 9 and 24 hours. Placebo led only to a mild non-significant reduction of the anxiety scale.

The sleep–inducing effects of oral progesterone were demonstrated in 9 healthy men (age 19-33), who received 300 mg progesterone. To investigate the effect of progesterone administration on sleep, electroencephalography (EEG) recordings, including sleep stage- specific spectral analysis, were made, and concomitantly plasma concentrations of progesterone, allopregnanolone and pregnanolone measured. Changes of sleep architecture and sleep EEG corresponded to those induced by agonistic modulation of the GABA receptors. Allopregnanolone and pregnanolone mediate these effects.

In 1976, Dalton published research showing that progesterone supplementation for progesterone-deficient pregnant women led to improved development of their children at one year, and greater academic achievements at 9-10 years and 17-20 years. The best academic results were achieved by those whose mothers received progesterone before the 16th gestational week, for treatment longer than 8 weeks, and for more than 5 grams of progesterone.

Trotter and co-authors supplemented progesterone and estradiol in premature babies to levels corresponding to time missed in the uterus. The treated babies had normal psychomotor development,  higher bone mineralization, and a reduction of lung diseases when compared to the untreated.

Progesterone deficiency appears to play a causal role in children with ADD or ADHS: Attention Deficit Disorder or Attention Deficit Hyperactivity Syndrome. Progesterone cream eliminated behavioral issues in a 9-year-old boy, who within 6 months, developed into one of the best students at his school, in all subjects. According to Platt, too little progesterone and too much insulin can cause ADD. Too little progesterone, too much insulin and too much noradrenalin causes ADHS. Correction of diet seems to play a role as well.

Progesterone has also been tried in multiple sclerosis. Progesterone supports remyelination by increasing the number of oligodendrocytes in the brain, leading to an increase in the myelin basic protein. And progesterone suppresses matrix metalloproteinases, which maintain inflammatory plaques in multiple sclerosis. The high levels of progesterone when pregnant explain why there is no MS-exacerbation during pregnancy.

Gonzales and co-authors published research showing that progesterone protects from spinal cord neuro-degeneration. Progesterone pellets had been administered to wobbler mice with severe neurodegeneration. This led to reduced cell-vacuoles and maintained mitochondrial structures. Treated mice had improved grip-strength and prolonged survival compared to the untreated. In 2007, after a successful study in rats, Wright and co-authors published their findings on progesterone in traumatic brain injury. In this study, 77 of 100 patients received IV progesterone (5mg/kg/hr/3 days) within 11 hrs after brain trauma. They showed a lower 30 day-mortality rate and moderate to good recovery of brain functions in cases of moderate traumatic brain injury, when compared to the 23 patients on placebo.

Xiao published a Chinese trial with 159 patients with Glasgow Coma Score </= ≤ 8. Within 8 hrs after brain trauma, 82 patients received IM progesterone (1mg/kg/every12hrs/5 days) and 77 received placebo. Patients on progesterone had a statistically significant lower 6 month-mortality rate (P>0.05) and a lower average intracranial pressure, 72 hours and 7 days after trauma. No side effects were seen on progesterone.

Progesterone was also studied in rats with stroke and led to less damage of the brain, improved blood-brain-barrier and fewer inflammation markers. Progesterone plus vitamin D given immediately after stroke led to better recovery. Three papers concerning the effect of progesterone on stroke in rats were published in 2009.

On March 15th of this year, enrollment opened for a multicenter trial in patients with brain trauma or stroke, at 17 hospitals in 15 states of the USA. The duration of the trial will be 5 years. Progesterone is given in a 96-hour continuous IV infusion. Dosing is quite complicated:

Loading dose = 0.714 mg/kg/hr x 1 hour 14.3 ml/hr

Maintenance infusion = 0.5 mg/kg/hr x 23 hours 10 ml/hr

Maintenance infusion = 0.5 mg/kg/hr x 24 hours 10 ml/hr

Maintenance infusion = 0.5 mg/kg/hr x 24 hours 10 ml/hr

1st taper = 0.375 mg/kg/hr x 8 hours 7.5 ml/hr

2nd taper = 0.25 mg/kg/hr x 8 hours 5 ml/hr

3rd taper = 0.125 mg/kg/hr x 8 hours 2.5 ml/hr

In cases outside of a trial I prefer the Chinese example: 1 mg progesterone per kg morning and evening, every 12 hours over 5 days.

Progesterone is also effective in epileptic seizures. In 25 women with complex partial (CPS) and secondary generalized motor seizures (SGMS) and low serum progesterone levels, (less than 5 ng/ml during the mid-luteal phase) received progesterone over 3 months. Of those, 18 (72%) experienced a decline in seizure frequency for CPS (p<0.01) and SGMS (p<0.02) compared to the 3 months prior to this therapy.

Progesterone can also have beneficial effects on the lungs. It increases pulmonary gas-exchange and reduces alveolar CO2 pressure. Asthma patients treated with progesterone report fewer asthma attacks. In my practice I have found that asthma patients treat with progesterone report fewer attacks, and overall patients report more undisturbed sleep and a significant reduction in snoring. Could sleep apnea be related to progesterone deficiency?

Other important properties and effects of progesterone include:




Bone-trophic (bone building)

Restores erections

Protects from prostate hyperplasia and prostate cancer

Supports thyroid function

Normalizes glucose, zinc, and copper levels

In cases of progesterone deficiency, adequate supplementation is not only justified, but a must. Trials in ADD, sleep apnea, multiple sclerosis, erectile dysfunction and especially in prostate hyperplasia (to avoid prostate cancer) are urgently required. Side effects are not to be expected if doses are adapted to individual needs. Immediate treatment with progesterone in brain trauma and stroke is already well substantiated.

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