Unravelling The Mystery of Baldness With Cyproterone Acetate

In the 2013 release of, HAIR LIKE A FOX, I hypothesized that castrated males were resistant to baldness because they had higher levels of progesterone, and lower levels of estrogen and prolactin, which cause metabolic stress. Progesterone not only supports mitochondrial energy metabolism (which appears to go off the rails in pattern hair loss), but also efficient blood circulation in the scalp, which is impaired in baldness. 

This runs counter to the dominant genetic-androgen theory of pattern baldness, which states that hair loss is an androgen-dependent condition. As I've written about, the idea that androgens are responsible for baldness has some serious issues. I will not rehash the arguments here, but this 26-minute video covers many of them.

Before the "big three" — and the death of holistic hair loss research in general — topical progesterone was a safe and somewhat effective treatment for baldness in both men and women.[1] The balding community is only now rediscovering the effects of progesterone, oddly enough through the use of of a birth control pill, Diane35, which contains a mixture of synthetic estrogen and progesterone.

Success with Diane35 is usually attributed to the estrogen content, or the "anti-androgen" effect, however, I have a different take.

I think the synthetic progesterone in Diane35, cyproterone acetate, is exerting its beneficial effects on hair growth despite the fact that the product contains estrogen, which exerts a net negative effect on hair growth. Similar to women reversing male-pattern baldness when they become pregnant,[2] men, who are willing to play Russian roulette with their sexual prowess, are demonstrating the restorative properties of progesterone on hair energy metabolism while embarking the road to transgenderdom.

WHEN ANTI-ANDROGENS ARE ANTI-ESTROGENS

One of the ways we can know that the progesterone-like component of Diane35 is responsible for hair growth, and not the estrogen or the anti-testosterone component, is that cyproterone acetate mimics castration, which is protective against baldness, dandruffacne, and prostate growth.[3]

Similarly, cyproterone acetate is an effective remedy for baldness,[4] dandruff,[5] acne,[6] and prostate enlargement.[7] Various anti-androgens are less effective, or not effective at all.[8, 9, 10] (Like baldness, androgens are often blamed for prostate enlargement. However, even when the supposed source of growth is completely eliminated, i.e., castration, the medical mind resorts to coining new terms, "castration-resistant prostate cancer," instead of reevaluating the situation.)

Part of the confusion surrounding the effects of cyproterone acetate is that it's referred to, almost exclusively, as an "anti-androgen." Cyproterone acetate is anti-testosterone, but in the process, it decreases estrogen to castration levels.[11]

Estrogen, the so-called female hormone, can antagonize the adrenals to produce "male" androgens.[12] Prostaglandins and nitric oxide — two inflammatory substances produced under the direction of estrogen — also stimulate the adrenals.[13] The accumulation of inflammatory prostaglandins and an the increased production of nitric oxide both have an inhibitory effect on hair growth by shifting cells to inefficient energy metabolism.[14,15]

SHOULD THE BALDING MALE TAKE PROGESTERONE?

I think everyone should experiment with everything, but there might be a better way...

Baldness is associated with an increase in total cholesterol and LDL.[16] Thyroid hormone — which is regulating the growth of hair — is a mirror image of total cholesterol.[17] Taking thyroid, which I'm beginning to believe should be part of anyone's anti-hair loss regimen, will increase the synthesis of progesterone by producing it from cholesterol. 

As I've mentioned a few times, Vidali et al. referred to thyroid hormones as "mitochondrial hair medicine" in 2013.[18]

Because there are so many factors working against the balding male, supporting respiratory "thyroid-driven" energy with nutrition seems reasonable, too. The MRDA of protein (i.e., 80-100 grams per day), an emphasis on sugars over starches, and avoiding an excess of phosphate in relation to calcium are basic things that can be done to shift energy metabolism in the right direction. Avoiding polyunsaturated fats in all forms (including fish oil) along with minimizing iron are additional nutritional strategies. 

While often characterized as some kind of pseudoscience, the resting pulse rate and body temperature reflect thyroid status.[19] If necessary, tests for thyroid stimulating hormone, cholesterol, prolactin, parathyroid hormone, albumin, carbon dioxide, vitamin D, ferritin, and iron saturation can be useful when things become too confusing. 

The main idea is to support the production of carbon dioxide through the mitochondria as shown below (i.e., oxidative metabolism).

REFERENCES

  1. Neuman, F., and Graf, K.J. Discovery, development, mode of action and clincal use of cyproterone acetate. "CA has been useful in treating androgen-dependent tumors and "androgenic" diseases such as idiopathic precocious puberty, hirsutism, and male-pattern baldness in adult females, all signs of virilization in females, hypersexuality in adult males, acne and seborrhea, baldness in adult males, and benign prostatic hypertrophy.” "Because of its strong progesterone potency…” "Gynecomastia sometimes develops temporarily in males treated with CA. Serious side effects of CA treatment have not been observed."
  2. Lynnfield, Y.L. Effect of pregnancy on the human hair cycle. J Invest Dermatol. 1960 Dec;35:323-7. “Little attention has been paid in medical literature to changes of the scalp hair during pregnancy. Bherman observed that women “with the seborrheic diatheses and even male pattern alopecia” improved at the end of the second month of gestation: 'Their scalps are less oily, and the sebum diminished to a normal amount, and the amount of hair fall is temporarily arrested.’”
  3. Hamilton, J.B. Male hormone stimulation is prerequisite and an incitant in common baldness. Am J Anat 71:451-480 1942
  4. Theodore, A., et al. Medical treatment of male pattern alopecia (androgenic alopecia). Head Neck Surg. 1985 Mar-Apr;7(4):336-9. "A therapeutic trial of topical progesterone at a 2%-5% concentration appears to be reasonable when the physician and patient appreciate the limitations of this approach."
  5. Burton, J.L., et al. Reduction of sebum excretion in man by the antiandrogen, cyproterone acetate. Br J Dermatol. 1973 Nov;89(5):487-90.
  6. Miller, J.A., and Jacobs, H.S. Treatment of hirsutism and acne with cyproterone acetate. Clin Endocrinol Metab. 1986 May;15(2):373-89.
  7. Geller, J., et al. Effect of cyproterone acetate on clinical, endocrine and pathological features of benign prostatic hypertrophy. Journal of Steroid Biochemistry, 1975. Vol. 6, pp. 837-843. "Clinical effects of CPA in patients with BPH. In five patients treated with CPA, 250 mg daily by mouth for two-to-four months, all improved clinically (Table 2) by both objective (residual urine and ability to void) and subjective criteria. The resected prostate was surprisingly small compared to the expected values estimated prior to drug treatment.” "The decrease in estrogen to the castration levels demonstrated in two patients during CPA therapy may reflect either a decrease in estrogen secondary to a decrease in testosterone which serves as a precursor for the estrogen, or it may reflect the direct inhibition of estrogen synthesis by Leydig cells. Since estrogen may stimulate squamous metaplasia and fibromuscular growth in the middle and lateral lobes of prostate, the usual anatomic sites of BPH, decreased estrogen production rates with CPA may have relevance to the clinical effects of the drug in BPH."
  8. Brajac, I. et al. Human Hair Follicle: An Update on Biology and Perspectives in Hair Growth Disorders Treatment. Hair Ther Transplant 4:115. "Recent years have witnessed a considerable progress in the research focused on treatment of hair disorders, but with limited success. Therefore, one of the prime challenges of modern hair research is a more profound understanding of the molecular controls of hair follicle cycling. Common diseases such as alopecia areata, telogen effluvium and AGA, until than will remain the unsolved medical problems."
  9. Leyden, J., et al. A systemic type I 5 alpha-reductase inhibitor is ineffective in the treatment of acne vulgaris. J Am Acad Dermatol. 2004 Mar;50(3):443-7. "Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function."
  10. Traish, A.M., et al. The Dark Side of 5α-Reductase Inhibitors’ Therapy: Sexual Dysfunction, High Gleason Grade Prostate Cancer and Depression. Korean J Urol. 2014 Jun;55(6):367-79. doi: 10.4111/kju.2014.55.6.367. Epub 2014 Jun 16."However, a substantial body of evidence exists which points to serious and potentially ill-health effects of 5α-RIs’ therapy. These include loss or reduced libido, erectile dysfunction, orgasmic and ejaculatory dysfunction, development of high grade PCa tumors, potential negative cardiovascular events, and depression. The side effects are potentially harmful in some individuals and in young men may be persistent or irreversible. The argument that the benefits of these drugs outweighs the risks is slowly eroding in the face of new emerging scientific evidence from preclinical and clinical studies."
  11. Geller, J., et al. Effect of cyproterone acetate on clinical, endocrine and pathological features of benign prostatic hypertrophy. Journal of Steroid Biochemistry, 1975. Vol. 6, pp. 837-843. "The decrease in estrogen to the castration levels demonstrated in two patients during CPA therapy may reflect either a decrease in estrogen secondary to a decrease in testosterone which serves as a precursor for the estrogen, or it may reflect the direct inhibition of estrogen synthesis by Leydig cells."
  12. Ditkoff, E.C., et al. The impact of estrogen on adrenal androgen sensitivity and secretion in polycystic ovary syndrome. J Clin Endocrinol Metab. 1995 Feb;80(2):603-7. "Adrenal hyperandrogenism is a common feature of patients with polycystic ovary syndrome (PCO). This may be due to enhanced adrenal sensitivity to ACTH. Because enhanced ovarian androgen secretion does not appear to explain this phenomenon, we explored the role of estrogen in inducing enhanced adrenal sensitivity, in that a state of relative hyperestrogenism exists in PCO" "In conclusion, these data provide evidence that estrogen is at least one factor that influences adrenal androgen sensitivity in PCO and may help explain the frequent finding of adrenal hyperandrogenism in this syndrome."
  13. Mohn, C.E., et al. The rapid release of corticosterone from the adrenal induced by ACTH is mediated by nitric oxide acting by prostaglandin E2. Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6213-8. "We demonstrated that both sodium nitroprusside (NP), a nitric oxide (NO) donor, and ACTH stimulate corticosterone release. NO mediated the acute response to ACTH because Nomega-nitro-l-arginine methyl ester, a NO synthase inhibitor, and hemoglobin, a NO scavenger, blocked the stimulation of corticosterone release induced by ACTH. NP stimulated prostaglandin E release, which in turn stimulated corticosterone release from the adrenal. Additionally, indomethacin, which inhibits cyclooxygenase, and thereby, prostaglandin release, prevented corticosterone release from the adrenal induced by both NP and ACTH, demonstrating that prostaglandins mediate acute corticosterone release."
  14. Garza, L.A., et al. Prostaglandin d2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. Sci Transl Med. 2012 Mar 21;4(126):126ra34.
  15. Wolf, R., et al. Nitric oxide in the human hair follicle: constitutive and dihydrotestosterone-induced nitric oxide synthase expression and NO production in dermal papilla cells. "These findings suggest NO as a signaling molecule in human dermal papilla cells and implicate basal and androgen-mediated NO production to be involved in the regulation of hair follicle activity."
  16. Arias-Santiago, S., et al. A comparative study of dyslipidaemia in men and woman with androgenic alopecia. Acta Derm Venereol. 2010 Sep;90(5):485-7. doi: 10.2340/00015555-0926. "A higher prevalence of dyslipidemia in women and men with androgenic alopecia has been found. The elevated lipid values in these patients may contribute, alongside other mechanisms, to the development of cardiovascular disease in patient with androgenic alopecia."
  17. Canaris, G.J., et al. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000 Feb 28;160(4):526-34. "The prevalence of abnormal biochemical thyroid function reported here is substantial and confirms previous reports in smaller populations. Among patients taking thyroid medication, only 60% were within the normal range of TSH. Modest elevations of TSH corresponded to changes in lipid levels that may affect cardiovascular health. Individual symptoms were not very sensitive, but patients who report multiple thyroid symptoms warrant serum thyroid testing. These results confirm that thyroid dysfunction is common, may often go undetected, and may be associated with adverse health outcomes that can be avoided by serum TSH measurement."
  18. Vidali, S., et al. Hypothalamic-Pituitary-Thyroid Axis Hormones Stimulate Mitochondrial Function and Biogenesis in Human Hair Follicles. J Invest Dermatol. 2013 Jun 27.
  19. Landsberg, L., et al. Is obesity associated with lower body temperatures? Core temperature: a forgotten variable in energy balance. Metabolism. 2009 Jun;58(6):871-6. doi: 10.1016/j.metabol.2009.02.017. "Changes in body temperature are associated with significant changes in metabolic rate."