Physicians Reference Manual – HRT for Women

Introduction:

Hormonal Replacement Therapy during postmenopause implies replacing something that is missing.  In order to know what and how much is missing, one must evaluate the levels of the deficient hormones in a physiological state of sufficiency (Fig. 1).  Steroid hormones fluctuate widely during the ovulatory cycle.  The luteal phase is considered a state of mini-pregnancy because the endocrine profiles mimics pregnancy and the purpose of the temporarily elevated levels of steroids during that phase is the preparation of the endometrium for implantation.  The early follicular phase has a carry-over from the late luteal phase of the previous cycle, and the late follicular phase is a time of rapidly changing steroid levels.  Since the purpose of steroid hormone replacement therapy during the postmenopause is not to induce menses, ovulation or pregnancy, but to prevent or reverse symptoms and signs of steroid hormone deficiency, peripheral levels of steroid hormones during the midfollicular phase are used as standard of sufficiency.

Administration of steroid hormones to postmenopausal women in amounts sufficient to bring peripheral levels within the range observed during the midfollicular phase is expected to prevent and reverse signs and symptoms of deficiency in most cases, while minimizing side effects from over dosage.  However, titration based on peripheral levels of steroids, clinical responses and side effects is required since many factors affect absorption, bioavailability and biological effects of steroid hormones.  The sensitivity to steroid hormones varies with target organs and the peripheral levels required for response in one target organ may be insufficient or excessive in another target organ.
 
These pages contain a concise presentation of the menopausal problems for which women seek medical assistance; background information on steroid hormones; and implementation of steroid hormone replacement therapy during the postmenopause based on published clinical studies.

Menopause:

Background Information

The menopause is a time in a woman’s life when the ovaries cease to function with resultant absence of monthly periods.  For probability and statistical reasons, a woman is not considered postmenopausal until after one year has elapsed since her last menstrual flow.  The perimenopause is the interval between the last regular menstrual flow and menopause; is characterized by irregular cycles with decreased frequency, quantity and duration of flow; and with duration of 2 to 7 years.
 
The three most common postmenopausal problems for which women seek medical assistance are:

Menopausal Symptoms

An estimated 75-85% of postmenopausal women develop symptoms of hypoestrogenism and these symptoms are severe and disruptive enough to require medical assistance in 15-25% of these women.  The author has tabulated an extensive list of symptoms in the format of a postmenopausal symptom questionnaire (PSQ), together with grading of severity and impact on marital, familial, social and work-related performance.  This questionnaire is available free of charge upon request.

Primary Postmenopausal Osteoporosis

Osteoporosis is a clinical syndrome characterized by a high susceptibility to bone fracture with resultant symptomatology, and due to excessive amount of bone loss, without any significant change in bone structure.   It is called secondary osteoporosis when there are known factors such as excess glucocorticoids, immobilization, and weightlessness.  It is called primary osteoporosis when there are no known factors and includes senile or age-related osteoporosis and postmenopausal osteoporosis (PPMO) (Fig. 2).  Senile osteoporosis occurs in the elderly of both sexes, being most common above age 70 years, and is characterized by loss of cortical and trabecular bones.  Hip fracture is the most serious and life threatening complication of senile osteoporosis.  PPMO occurs only in women, with radiologic evidence of rapid loss of trabecular bone during the first decade following menopause.  Because the bone loss in PPMO is predominantly trabecular bones such as the vertebrae and the distal forearm.

Cardiovascular Problems

Cardiovascular problems occur more frequently in men than premenopausal women, due to the protective effect of estrogens and certain adrenal androgens.  However, there is an increased prevalence and incidence of cardiovascular complications in older postmenopausal women, probably due to decreased ovarian and adrenal steroids.
 
Although adequate nutrition and change in lifestyle play an important role in the management of postmenopausal problems, some postmenopausal women may require steroid hormone replacement therapy in conjunction with a dietary program in order to effectively control some postmenopausal problems.

Steroid Hormone Chemistry:

A brief review of chemistry, biochemistry, physiology, and clinical effects of steroids will be presented as a basis for steroid hormone replacement therapy during the postmenopause.

Biochemistry of Steroids

 
 
All steroids derive from cholesterol.  That is why drugs that block the synthesis of cholesterol may affect adversely in the synthesis and availability of important steroid hormones.  In the nonpregnant woman, the adrenal cortex and the ovary are the only significant sources of steroid hormones.  The first step in the synthesis of steroid hormones from cholesterol is the side chain cleavage of this steroid to yield pregnenolone.  Depending on the concentration of enzymes, cofactors, substrates, and endproducts, and other factors, the adrenal cortex and the ovary use different pathways from pregnenolone for the synthesis of steroid hormones. 

Ovarian Synthesis of Steroids

In the ovary, the three functional units are: the follicle, the corpus luteum and the stroma (Fig. 4).  Each unit uses a different pathway for the synthesis of progesterone, androgens, and estrogens.  In the follicle, the pathway is via:  Pregnenolone → 17-Hydroxypregnenolone → 17-Hydroxyprogesterone → Androstenedione → Estrone ← Estradiol-17β, with Estradiol-17β as the most important biologically active estrogen.  This pathway is under the influence of FSH which stimulates aromatization of androgens to estrogens, acting on aromatase enzymes in the follicle. The follicular phase is estrogenic.  In the corpus luteum, the pathway is from Pregnenolone to Progesterone under the influence mainly of LH.  The luteal phase is progestogenic.  In the stroma, the pathway is via the triangle (Exp5) route from the Pregnenolone → 17-Hydroxypregnenolone → 17-Hydroxyprogesterone → Androstenedione → Testosterone.  Aromatization is absent in the stroma due to lack of aromatase enzymes.  The stroma is androgenic, under the influence of LH and also insulin.  One would expect therefore that chronic elevation of LH and/or insulin would result in ovarian hyperandrogenism.  Such is the case in polycystic ovarian disease (PCOD).  Hyperinsulinemia is a possible mechanism by which increased simple carbohydrate intake could result in hyperandrogenism and menstrual disturbances.  The predominant steroid synthesized by the stroma is androstenedione with lesser amount of testosterone and dehydroepiandrosterone.

Adrenal Synthesis of Steroids

The adrenal cortex contains 3 distinct zones (Fig. 5): the zona glomerulosa, under the control mainly of renin-angiotensin system and to a lesser degree ACTH.  The zona glomerulosa secretes predominantly mineralocorticoids, aldosterone being the most potent; the zona fasciculate is under the influence of ACTH, and produces glucocorticoids, with predominant output of cortisol; the zone reticularis is under ACTH control, but also under modulation by other unknown factors, and secreting mainly the androgens dehydroepiandrosterone (DHEA).  The only adrenal zone influenced significantly by aging and menopause is the reticularis with marked decrease secretion of DHEA and DHEA-S.  Therefore, these adrenal androgens are the most important to consider in the management of menopause.

Metabolism of Steroids

After synthesis, the steroid hormones are secreted into the peripheral circulation mostly bound to plasma proteins, and reach the target tissues where they exert their effect.  The androgens and estrogens bind to Sex Hormone Binding Globulins (SHBG) whereas progesterone and cortisol bind to transcortin.  SHBG and transcortin are synthesized in the liver and their production is increased by estrogens.  High doses of progesterone can displace cortisol, with increased free biologically active cortisol, resulting in glucocorticoid effects of pharmacological dose of progesterone: catabolic, glycemic and immunosuppressive effects.  Peripheral progesterone is used as a precursor for the synthesis of renal and adrenal mineralocorticoid, catabolic, glycemic and immunosuppressive effects.  For these reasons, progesterone replacement therapy during postmenopause should not be used alone but in conjunction with the anabolic estrogens and the immune stimulating adrenal androgens.
 
 
The peripheral metabolism of steroid hormones by the liver, gut, skin and other tissues involves mainly oxidation, reduction and conjugation to sulfates and glucuronides.  The sulfokinase activity of the liver is very efficient.  For example, following an oral dose of DHEA, the increase in serum DHEA-S levels is 1000 times higher than the increase in serum DHEA due to efficient sulfation by the liver.  Except for DHEA-S, conjugated steroids are usually biologically inactive.  However, they serve as prohormones in target organs that are capable of enzymatic hydrolysis of the conjugates to liberate the free biologically active steroid hormones at the site of action.
 
Peripheral unconjugated steroids exist in 2 forms: free (unbound) and bound to specific plasma proteins.  Only the small fraction of free steroid hormones (unbound to specific plasma proteins) is biologically active.  In the premenopausal woman, only about 1-2% of peripheral androgens and estrogens are available for binding to receptors in target cells. 

HRT Implementation:

Hormone replacement therapy during the postmenopause should be individualized, based on symptomatology and prevention aims.  Since the ovary secretes estrogens, androgens, and progesterone, evaluation of postmenopausal women for hormonal replacement therapy should include all 3 steroids.  The adrenal androgens DHEA and DHEA-S are markedly decreased following menopause.  These androgens should therefore be considered in a comprehensive approach to the management of the postmenopausal woman.  The dosage and combinations can be adjusted, taking into account blood levels, remission of symptoms, and side effects.  Adverse effects on lipid profile, insulin sensitivity, the cardiovascular system and carcinogenic effects on the endometrium and breasts should be monitored closely.
 
Guy E. Abraham, MD and John C. Hakala, RPh - 2007
 
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