Menopause: Current Concepts Chittaranjan N Purandare, Suvarna S Khadilkar
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Hormones at MenopauseChapter 1

Pankaj Desai
Ranu Patni
 
INTRODUCTION
Hormones extensively govern all the menstrual phases in life of a woman. It is therefore pertinent to know what these subtle changes at menopause are. This helps one to understand the pathophysiological basis of many changes in menopause. It also helps one to understand the basis of administering different agents for hormone replacement therapy in menopause.
 
GONADOTROPINS AT MENOPAUSE
Shortly after the menopause, one can safely say that there are no remaining ovarian follicles.2 Eventually there is a 10-20 fold increase in FSH and approximately a 3-fold increase in LH, reaching a maximal level 1-3 years after menopause, after which there is a gradual, but slight, decline in both gonadotropins.3,4 Elevated levels of both FSH and LH at this time in life are conclusive evidence of ovarian failure. FSH levels are higher than LH because LH is cleared from the blood much faster (initial half-lives are about 20 minutes for LH and 3-4 hours for FSH), and perhaps because there is no specific negative feedback peptide for LH like inhibin.
 
ANDROGENS AT MENOPAUSE
The postmenopausal ovary secretes primarily androstenedione and testosterone. After menopause, the circulating level of androstenedione is about one half of that seen prior to menopause.5 Most of this postmenopausal androstenedione is derived from the adrenal gland, with only a small amount secreted from the ovary, although androstenedione is the principal steroid secreted by the postmenopausal ovary.6 Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), originating in the adrenal gland, decline markedly with aging: in the decade after menopause the circulating levels of DHEA are approximately 70 percent less and levels of DHEAS are about 74 percent less than levels in young adult life7 (Table 1.1).
Testosterone production decreases by approximately 25 percent after menopause, but the postmenopausal ovary in most women, but not all, secretes more testosterone than the pre-menopausal ovary. With the disappearance of follicles and estrogen, the elevated gonadotropins drive the remaining stromal tissue in the ovary to a level of increased testosterone secretion.
2
Table 1.1   Blood production rates of steroids12
Reproductive
Postmenopausal age
Oophorectomized
Androstenedione
2-3 mg/day
0.5-1.5 mg/day
0.4-1.2 mg/day
Dehydroepiandrosterone
6-8
1.5-4.0
1.5-4.0
Dehydroepiandrosterone
8-16
4.9
4.9
sulfate
Testosterone
0.2-0.25
0.05-0.18
0.02-0.12
Estrogen
0.350
0.045
0.045
Suppression of gonadotropins with gonadotropin-releasing hormone (GnRH) agonist or antagonist treatment of postmenopausal women results in a significant decrease in circulating levels of testosterone, indicating the gonadotropin-dependent postmenopausal ovarian origin.810 The total amount of testosterone produced after menopause, however, is decreased because the amount of the primary source, peripheral conversion of androstenedione, is reduced, The early postmenopausal circulating level of androstenedione decreases approximately 62 percent from young adult life.7 The menopausal decline in the circulating levels of testosterone is not great, from no change in many women to as much as 15 percent in others.l,4,7 Nevertheless, compared with young women, the overall androgen exposure of perimenopausal women to androgens is less.11
 
ESTROGENS AT MENOPAUSE
There is a major decrease in serum estrogens in the perimenopause and in the immediate postmenopausal period12 with little change occurring in the subsequent years. After the final menstrual period, there is very little ovarian contribution to serum concentrations of sex steroids. Women with a history of bilateral oophorectomy show little difference in serum levels of estrone, estradiol, or testosterone when compared with women undergoing a natural menopause.13 Androstenedione levels were actually higher in women with oophorectomy than their menopausal cohort. This is perhaps counterintuitive, but highlights the very low metabolic activity of the postmenopausal women.
Postmenopausal women have serum estradiol levels below 15 pgml and mean estrone levels of about 30 pg/ml.13 Although estradiol levels are negligible in the menopausal ovary, it has been frequently observed that estrone levels are higher in older men and women than in younger adults. Older women convert androstenedione to estrone more efficiently than young women. In keeping with this observation, adipose tissue aromatase mRNA expression also increases two-fold to four-fold between age 20 and 60.14,15 Adipose mRNA expression is highest in the hip fat and lowest in the abdomen.15 Aromatase expression also occurs to a large degree in the skin, and to a lesser degree in bone, brain, and breast. Age and time since the final menstrual period are not significant predictors of sex hormone concentrations.
3
Table 1.2   Change in circulating hormone levels at menopause
Pre-menopause
Post menopause
Estradiol
40-400 pg/ml
10-20 pg/ml
Estrone
30-200 pg/ml
30-70 pg/ml
Testosterone
20-80 ng/dl
15-70 ng/dl
Androstenedione
60-300 ng/dl
30-150 ng/dl
The circulating estradiol level after menopause is approximately 10-20 pg/ml, most of which is derived from peripheral conversion of estrone, which in turn is mainly derived from the peripheral conversion of androstenedione.5,1316,1417 The circulating level of estrone in postmenopausal women is higher than that of estradiol, approximately 30-70 pg/ml. The average postmenopausal production rate of estrogen is approximately 45 mg/24 hours, almost all, if not all, being estrogen derived from the peripheral conversion of androstenedione (Table 1.2). The androgen: estrogen ratio changes drastically after menopause because of the more marked decline in estrogen, and an onset of mild hirsutism is common, reflecting this marked shift in the sex hormone ratio. With increasing age, a decrease can be measured in the circulating levels of dehydroepiandrosterone sulfate (DHEAS) and dehydroepiandrosterone (DHEA), whereas the circulating postmenopausal levels of androstenedione, testosterone, and estrogen remain relatively constant.4,5
Estrogen production by the ovaries does not continue beyond the menopause: however estrogen levels in postmenopausal women can be significant, principally due to the extra glandular conversion of androstenedione and testosterone to estrogen. The clinical impact of this estrogen will vary from one postmenopausal woman to another, depending on the degree of extra glandular production, modified by a variety of factors.
The percent conversion of androstenedione to estrogen correlates with body weight. Increased production of estrogen from androstenedione with increasing body weight is probably due to the ability of fat to aromatize androgens. This fact and a decrease in the levels of sex hormone-binding globulin (which results in increased free estrogen concentrations) contribute to the well-known association between obesity and the development of endometrial cancer. Body weight, therefore, has a positive correlation t with the circulating levels of estrone and estradiol.5 Aromatization of androgens to estrogens is not limited to adipose tissue: because almost every tissue tested has this activity.
Eventually, the ovarian stroma is exhausted and, despite huge reactive increments in FSH and LH, no further steroidogenesis of importance results from gonadal activity. The postmenopausal ovary weighs less than 10 g, but it can be visualized by ultrasonography.18
With increasing age, the adrenal contribution of precursors for estrogen production proves inadequate. In this final stage of estrogen availability, levels are insufficient to sustain secondary sex tissues.4
 
IN SUMMARY
In summary, the symptoms frequently seen and related to decreasing ovarian follicular competence and then estrogen loss in this protracted climacteric are:
  1. Disturbances in menstrual pattern, including an ovulation and reduced fertility, decreased flow or hypermenorrhea, irregular frequency of menses, and then ultimately, amenorrhea.
  2. Vasomotor instability (hot flushes and sweats).
  3. Atrophic conditions: atrophy of vaginal epithelium: formation of urethral caruncles: dyspareunia and pruritus due to vulvar, introital, and vaginal atrophy: general skin atrophy: urinary difficulties such as urgency, bacterial urethritis and cystitis.
  4. Health problems secondary to long-term deprivation of estrogen: the consequences of osteoporosis and cardiovascular disease.
A precise understanding of the symptom complex the individual patient may display is often difficult to achieve. Some patients will experience severe multiple reactions that may be disabling. Others will show no reactions, or minimal reactions, that go unnoticed until careful medical evaluation.
It is helpful to classify hormonal problems in 2 categories:
  1. Those associated with relative estrogen excess such as dysfunctional uterine bleeding, endometrial hyperplasia, and endometrial cancer.
  2. Those associated with estrogen deprivation such as flushes, atrophic virginities, urethritis, and osteoporosis.
Subsequent chapters will deal with how each of these occur and how does one handle these problems in clinical practice.
MCQS “Hormones At Menopause” (SS Khadilkar)
1. 1-3 years after menopause Serum FSH levels:
  1. Rise by 10 to 20 fold
  2. Rise 3 fold
  3. Decreases to minimum
  4. Reduces to half
2. 1-3 years after menopause Serum LH levels:
  1. Rise by 10 to 20 fold
  2. Rise 3 fold
  3. Decreases to minimum
  4. Reduces to half
3. Rise in SLH levels postmenopausally is less pronounced than the FSH because:
  1. LH has a short half life
  2. FSH has a specific negative feedback peptide like inhibin
  3. Both A and B are true
  4. None of the above
4. Postmenopausal ovary secretes:
  1. Androstenedione and estrogen
  2. Androstenedion and testosterone
  3. Estrogen and testosterone
  4. None of the above
5. Androstenedione circulating in blood of post menopausal women:
  1. Is half that seen in premenopausal women
  2. Is derived mainly from adrenally
  3. 5Is only partly from ovary
  4. All of the above are correct
6. After menopause testosterone production decreases by approximately:
  1. 25%
  2. 10%
  3. 75%
  4. No change at all
7. A decade after menopause circulating levels of DHEA are:
  1. 70% less than in young adult life
  2. Same as in immediate postmenopausal phase
  3. Doubled than levels in young women
  4. None of the above
8. The circulating castradiol levels in post menopausal women are:
  1. 100-200 pg/ml
  2. 10-20 pg/ml
  3. Nil
  4. 50 pg/ml
9. Post menopausal production of estrogen is 45 mg/24 hours which is derived:
  1. Secretion from ovaries from
  2. Peripheral conversion from androsterilization
  3. Both A and B
  4. None of the above
10. Aromatization of androgens to estrogen:
  1. is limited to adipose tissue only
  2. is only documented in bone breast
  3. is documented in almost every tissue
  4. All of the above
ANSWERS
1 a
2 b
3 c
4 b
5 d
6 a
7 a
8 b
9 b
10 c
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