What is "Intracrinology"?  Is it different from "Endocrinology"?  The two words appear to imply the same concept one using a qualifier of Latin origin, "intra", the other of Greek origin, "endo", both with the same translation, namely “inside” in a dictionary of etymology.

In the practice of medicine these two words refer to two very different sets of knowledge and subsequently to two different clinical approaches to the patient.  Endocrinology deals with the secretion of hormones by well-known endocrine glands: the pituitary, ovaries, testes, thyroid, pancreas and others. The hormones are normally secreted into the blood where their concentrations can be measured by now well-established methods.  Our knowledge of this multi-organ endocrine system goes back to the early 1920s. 

Intracrinology refers to a more recent concept, namely the observation that multiple tissues can synthesize androgens and estrogens using the inactive molecule dehydroepiandrostenedione (DHEA) as the intracellular sex steroid precursor.  Dr. Fernand Labrie introduced the word Intracrinology in 1991 in the first of a series of seminal papers defining this unique steroidogenic mechanism and its physiologic role in men and women. He and collaborators have shown that, at menopause, women not only start missing estrogens produced by the ovary but also those produced normally and originating from the metabolism of the molecule DHEA in various tissues.  These androgens and estrogens exert their action in the same cells in which they are synthesized and eventually inactivated.

This book describes extensively the physiologic and pharmacologic use of DHEA (or prasterone) in postmenopausal women and its local effects on various tissues such as bone and the vaginal wall with no effect on the endometrium.

The scientific principles of Intracrinology are now well established and are increasingly a part of the daily practice of clinical medicine.

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EXECUTIVE SUMMARY

A fundamental observation is that the secretion of estradiol by the ovaries stops at menopause (Figure 1).

Figure 1:  Two very different sources of sex steroids are present in women: (1) Estrogens and testosterone from the ovaries which stop secretion at menopause, and (2) DHEA (Dehydroepiandrosterone, also known as prasterone) becomes, at menopause, the only source of both androgens and estrogens in the body of women. These two sex steroids are made exclusively inside the cells of some but not all peripheral tissues according to the local needs and have no biological influence outside these cells.

 
On the other hand, DHEA (dehydroepiandrosterone or prasterone), the inactive precursor of sex steroids, is transformed inside select cells into small amounts of estrogens and androgens by the highly-sophisticated mechanisms of Intracrinology with no systemic biological activity arising from the very low concentrations of estrogens and androgens in the blood (Figure 2).

Figure 2:  A schematic representation of the metabolism of DHEA, the precursor of sex steroids following its uptake into vaginal cells.  Very small amounts of estradiol (E2) and of the androgens, testosterone and dihydrotestosterone (DHT), are made and inactivated intracellularly by the steroidogenic and steroid-inactivating enzymes of the intracrine pathways while biologically inactive concentrations of estrogens and androgens diffuse into the circulatory system, thus avoiding systemic effects outside the vagina. (4-dione, androstenedione; A-dione, 5-androstane-3,17-dione; ADT, androsterone; E1, estrone; E2, 17-estradiol; 5-diol, androst-5-ene-3, 17-diol; HSD, hydroxysteroid dehydrogenase; testo, testosterone; ADT, androsterone; ADT-G, androsterone glucuronide; ADT-S, androsterone sulfate) (Labrie 2015).

A resulting fundamental observation is that menopause is not the end of the need for both estrogens and androgens in women. Quite the contrary, research conducted at Endoceutics has shown that after menopause, both estrogens and androgens continue to be made in highly specific amounts in the peripheral tissues that are in need of one or both of these sex steroids. In fact, DHEA, mainly from the adrenal glands and to some extent from the postmenopausal ovary, is the only source of intracellular estrogens and androgens after menopause (Figure 3).

Figure 3: Prior to menopause, the ovaries provide approximately 20% of DHEA to peripheral tissues and the adrenal glands contribute approximately 80% of DHEA to the peripheral tissues. After menopause, DHEA is the unique source of sex steroids. (KEY: ACTH: adrenocorticotropic hormone; CRH: corticotropin-releasing hormone; DHEA: dehydroepiandrosterone; E2: estradiol; FSH: follicle-stimulating hormone; LH: luteinizing hormone; GnRH: gonadotropin-releasing hormone; T: testosterone.)

This discovery represents a major contribution to medical science and women’s health. While the estrogen estradiol, following its release into the circulatory system from the ovary, indiscriminately stimulates all tissues which possess estrogen receptors, DHEA requires a sophisticated transformation, which is cell and tissue-specific, ranging from no estrogen formation in the endometrium to variable levels of cell-specific transformation in other cell types.

The control of DHEA action in the peripheral tissues is therefore much more sophisticated and rigorously controlled (Figure 4A) than the relatively simple action of estradiol (Figure 4B). While the actions of DHEA have recently been demonstrated in the vaginal wall⁶, it is reasonable to believe that the cell-specific control of DHEA transformation plays a major role in the physiological functioning of most human tissues.⁷

Figure 4A/4B: Intracellular availability of sex steroids after conversion from DHEA is finely controlled by multiple enzymatic steps, whereas estradiol has direct effects on nuclear receptors based on endogenous systemic concentrations (pre-menopause) and the level of exogenous dosing (after menopause) with limited intracellular control over total exposure.

After menopause, a combination of the action of the sophisticated pathways of intracellular androgen and estrogen biosynthesis from DHEA coupled with the intracellular inactivation of the sex steroids at their site of biosynthesis in target tissues eliminates any biologically significant change in the very low concentration of circulating estrogens and androgens, thus avoiding influence on any other tissues (Figure 5). Consequently, the application of intravaginal DHEA, a truly bio-identical molecule, for the treatment of dyspareunia associated with vulvovaginal atrophy or genitourinary syndrome of menopause (GSM) is simply mimicking the physiological mechanism of action of endogenous DHEA.

Figure 5: Maintenance of serum estradiol at biologically inactive concentrations after menopause in women.  Following a ≥ 95% decrease in circulating estradiol in postmenopausal women, serum estradiol is maintained at an average of about 4 pg/ml with an upper limit of normal of 9.3-10 pg/ml¹¹. Data are presented as means ± SD.  Such low levels of circulating estradiol are well below the threshold of estrogenic activity and have no biological relevance; with this mechanism, stimulation of cell proliferation in the uterus and other inappropriate tissues is avoided after menopause.

This precursor steroid avoids the risks of systemic estrogenic or androgenic side effects. The endometrium (inside lining of the uterus) is the best known example of this: while the administration of estradiol exerts stimulatory effects on the endometrium, potentially leading to endometrial carcinoma, DHEA has absolutely no effect on the endometrium¹⁶.

Since practically all body functions are modulated, to various degrees, by estrogens and androgens^3,4, it is important to realize that a complete absence of sex steroids after menopause would have a serious negative impact on the quality of life of post-menopausal women. Nature has avoided such a situation with the evolution of DHEA over millions of years, as a secondary source of sex steroids – a phenomenon particularly important after menopause following cessation of ovarian estradiol secretion.

The intracrine system protects against a lack of local sex steroid availability after menopause. Unfortunately, the availability of DHEA, the exclusive source of both estrogens and androgens after menopause, markedly decreases with age thus resulting in a decrease in local, Intracrine-mediated estrogen and androgen formation in select peripheral tissues (Figure 6).

Figure 6: The concentration of DHEA, mainly secreted by the adrenal glands, decreases starting at the age of 30 years and has already lost, on average, 60% of its value by the age of 50 years, or at the onset of menopause. Serum DHEA continues to decrease thereafter.

Accordingly, as age advances and DHEA secretion continues to decrease, the signs and symptoms of vaginal atrophy become more severe, although somewhat variable between women due to different serum levels of remaining endogenous DHEA and different tissue sensitivity to DHEA. The vagina is particularly sensitive to sex steroids; a lack of androgens and estrogens due to decreased serum DHEA concentrations leads to problems in at least 50% of post-menopausal women, which consequently has a major impact on quality of life, sexual function, and relationships.

There are many terms for this condition affecting vaginal and genitourinary health. One is vulvovaginal atrophy (VVA). Recently, the term genitourinary syndrome of menopause (GSM) has been introduced in order to more fully describe the signs and symptoms resulting from atrophy of the genital and urinary systems that take place with menopause.

When considering vaginal anatomy, morphology, physiology and pathology both estrogens and androgens are required for normal vaginal function¹³. Therefore, replacement treatment with estrogen alone is a partial or incomplete treatment, since the lack of androgens is not taken into account and the full complement of local hormones are not restored.  An efficacious, complete, and safe treatment for GSM/VVA, must consider the above physiology, as well as maintain blood concentrations of estradiol below the upper limit of the normal postmenopausal range (9.3-10.0 pg estradiol /mL) as measured by mass spectrometry assays validated according to the Food and Drug Administration (FDA) guidelines^10,11,2,15.  (See Figure 5 above)

Although some previous recommendations have suggested that the upper limit of normal serum estradiol could be 20 pg estradiol /mL, such an abnormally elevated concentration derives from measurements using less specific immuno-based assays which give values approximately 100% too high^1,8,9,12.

With intravaginal DHEA, there is no biologically significant leakage of active sex steroids into the circulatory system^8,9,11,14. The intracrine system, developed over millions of years of mammalian evolution provides a unique mechanism for the generation of local sex steroids though-out life. This tissue-specific, exclusively intracellular, system assumes paramount importance after menopause and ovarian arrest. In the majority of post-menopausal women where an age-related decline in adrenal DHEA production has occurred along with the complete loss of ovarian estrogen, the intravaginal administration of a small amount of DHEA increases local DHEA availability and action exclusively in the vagina, where the symptoms of sex steroid deficiency occur, with no influence on other tissues.

Now Test Your Knowledge of Topics to be Covered in the eBook
and and Earn 5 AxiaMerits

1. All of the following statements are true except for: 

(A) The renin angiotensin aldosterone system (RAAS) works via intracrine pathways.

(B) Dehydroepiandrosterone (DHEA) and its sulfated form (DHEA-S) are the most abundant steroid hormones in human circulation.

(C) Animal models reveal that intravaginal DHEA may rejuvenate tissue in all three layers of the vaginal wall.

(D) The most common adverse event found in studies with intravaginal DHEA is headache.

(E) Both (A) and (C) are false.

(F) All the above statements are true.

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