Thursday, September 23, 2010

8.23 Menopausal Hormone Treatments To Do or not To Do?

Physician's Notebooks 8 - - See Homepage

23. Hormones and Menopause – HRT in Women - Update 19 March 2018
Hormone (Replacement) Therapy (HT or HRT) is part of Notebooks healthy longevity program. Ideally, on HT one stays younger longer but lifespan is not necessarily increased. HT is experimental and has risk. The sex hormones are, for women, estrogen (estradiol, E2, or its derivatives) and for men androgen (testosterone, TE, or its derivatives). Both are growth stimulants for sexual tissue; they promote bone and muscle strength, and improve brain function that favors motivation, epithelial secretion that helps lubrication, and skin hydration that slows wrinkling. The effects are to preserve vigor, youthful appearance, sexual activity and attractiveness. The hormone given to older person should not be aimed to restore a 20- or 30-year-old's vigor and mentality; rather it should preserve the age-level of a 45- to 55-year-old.
   Hormone Therapy has mostly been given to women because female cessation of sex hormone comes early and is dramatic, occurring between ages 45 and 55 or earlier after removal of ovaries so we have more experience in women. In men, it is more experimental and less necessary because men experience more gradual cessation of sex hormone secretion and still have significant level of androgen at age 70. At age 85 I have not yet needed it. Also there is the big problem of stimulating prostate cancer. So male HT is started, if at all, only after very low testosterone level and with strong consideration of its bad effects and at an older age than female HT.
   In mother’s womb, a female fetus is exposed to high estrogen. But after birth in a young child there is very low sex hormone. By age 9 the developmental biologic clock plus external environment result in certain cells in brain's hypothalamus starting to make gonadotropin releasing hormone (GRH), which gets to cells in anterior pituitary gland and starts them producing follicular stimulating hormone (FSH). This increases gradually in girls ages 9 and 12 and then the FSH rises high enough to start stimulating ovarian cells to make estradiol (E2). As E2 rises in blood, it stimulates growth in female sexual tissue to start the changes of puberty and inhibit pituitary release of FSH. This sets up the 1st sexual hormone cycle: Over 4-week intervals, FSH rises, stimulating ovaries to release E2, which rises and, by mid-point of cycle, feeds back to inhibit pituitary release of FSH. During each monthly cycle is seen a rise and fall of FSH then a rise of E2 and fall, during 2nd half of monthly cycle. At the cycle's end a menstruation occurs as the stimulated uterine lining cells are deprived of E2. This early menstruation, from ages c.13 to 17, may be heavy, painful  and irregular. Next event, starting irregularly is monthly ovum (plural, ova) release by ovulation by one or the other ovary. By ages 18 to 20 most women are ovulatin.
   Now, look at ovum development. Every ovum in a woman’s 2 ovaries (est. 300,000 ova) is already in place at birth. The ova are inactive, each ovum surrounded by nourishment cells in a follicle (little bubble with nourishing liquid). So a girl starts with 300,000 inactive ova in 2 ovaries, each ovum in pre-follicle package. The stimulus for an ovulation is the biologic clock plus the hormonal milieu of the early FSH-E2 cycle interacting with external stimuli.
   Initial stimulus for ovum release is production in hypothalamic brain cells of luteinizing releasing hormone (LRH), which passes down nerve fibers to anterior pituitary gland to stimulate cells to produce luteinizing hormone (LH). The secretion of LH occurs in a burst within minutes. It causes an ovum in one follicle to burst from surface of its ovary in a rupture of the follicle, releasing the ovum, which is immediately sucked into end of uterine tube in a condition for fertilization by sperm.
   At same time of ovulation, which occurs 12 to 14 days after first day of last menstruation, the follicle cells start producing a second ovarian hormone, progesterone, during last 2 weeks of the ovulation menstrual cycle and its effect is to get the uterine lining cells ready for implantation of the fertilized ovum. If no fertilized ovum implants by 25th day after start of last menstruation, the ruptured follicle stops making progesterone and a post-ovulation menstruation occurs from withdrawal of hormones. The estrogen-progesterone menses are more predictable, shorter and less painful than the earlier menses of E2 alone.
   In talking about a daily point in menstrual cycle, it is useful to call the first day of seeing blood “day-1” and count successive days until the next 1st day when a new day-1 starts the next cycle. Thus, a 29-day cycle is numbered from day-1 to day-29, and day-15 would be its exact midpoint.
   The E2 exerts the estrogenic effect that feminizes physically and mentally. Additionally it is important in mineralizing bones and in its absence osteoporosis worsens. It also has effect on non-sexual tissues, like growth hormone, and stimulates glands and causes tissues to be well oiled and hydrated. This explains dryness and relative dehydration of tissue in old women. Also it lowers LDL-cholesterol, a good effect against heart disease. But it slightly speeds clot formation in blood, a bad effect because this ups the risks of a blood clot traveling to lung (pulmonary embolus), or of myocardial infarction heart attack or stroke. Another possible bad effect of E2 is its growth-hormone action on sexual tissue and risk of breast and uterus cancer.
   Progesterone has more localized effect – mostly on uterus. It matures the uterine lining to accept implantation of fertilized ovum; also this maturing effect makes for a more predictable, lighter and less discomforting bleeding than initial menstruation. This maturing effect is anti-cancer and types of progesterone are used against uterine cancer.  However, some of the medicines used to replace progesterone in HRT may increase risk of breast cancer. Progesterone’s extra-genital effect is to slightly elevate and increase LDL cholesterol, a No go for the heart. Progesterone also causes a rise in basal body temperature, a detecting sign of its presence from ovulation.
   The Gonadotropin Releasing Hormone (GRH) and FSH & LH have only local effects on target tissue – the pituitary cell affects GRH and the ovary affects FSH and LH.  In very old age, E2 levels drop very low and FSH & LH production is over-stimulated leading to very high FSH and LH in blood. That may explain adverse mental effect in the years after menopause and also ovarian tumors in older women.
   Hormone levels of normal fertile women age 15 to 45 vary depending on time in the cycle. At start, during bleeding, E2 is c.40 picogram/ml serum and during mid-cycle it may peak to 300 pg. Progesterone is undetectable until after ovulation, and peaks to 2.5 nanogram/ml (ng is 1000 times higher than a picogram but the effects completely different). FSH is 1-9 milli-IU/ml during menstruation and peaks at 6–26 at mid-cycle, and LH is 1–2 milliU/ml during menstruation and peaks at 16–104, just before ovulation.
   After menopause, E2 and Pr drop toward zero (E2 more slowly; in younger post menopause it is 10 to 20) and the feedback mechanism stimulates the pituitary to over produce and release FSH & LH, which typically each rise above 100 units in very old age.
   "Menopause" is when menses finally stop, but has several years of progressive ovaries’ failure that starts with a lowering frequency of ovulation, progresses to dropping E2 and rising FSH and LH with the irregular bleeding that this causes, and terminates in stop of menstruation, and E2 below 10 pg/ml and FSH and LH above 50 IU. In post-menopause, comes involution of body and mind with hot flashes and osteoporosis fracture, vaginal dryness, and emotional changeability & mental negativity.  The whole process - menopause and everything that goes with it - is called the climacteric.
   Why menopause? The data point to end-organ failure – the ovaries. Certainly, ovaries stop responding to FSH and LH, and, most importantly, E2 production drops. (A small amount of E2 continues to come from adrenal glands) The dropping, very low E2 in blood is sensed by the pituitary and it responds by overproducing FSH and LH. (Levels as high as 300 are seen in very old age) But the normal effect of FSH and LH on the ovary is gone – the analogy of beating a dying horse is apt here. The apparent cause of ‘premature’ ovarian failure (It is the only organ that fails many years before natural lifespan) seems to be trauma of 30 yrs of monthly ovarian follicle rupture with resulting scars. Ovulation literally tears the ovaries to death.
   Comparing naturally aging women to similar age men, the women age more rapidly starting at menopause and the difference between the sexes in this age period is that male gonads (testes) continue to produce significantly higher amounts of the androgen testosterone (TE) even into 8th decade while ovaries fail in fifth decade.
   The multiple effects of menopause are well-known. Of equal or greater importance is long term general organ system effect – advancing osteoporosis and arthritis leading to premature easy fracture and disabling joint disease, the advancing arteriosclerosis that not only affects a woman’s heart but adds to the risk of senile dementia; also an aging of skin and wrinkle, and unsightly pouch and dowager hump.
The rationale for estrogen treatment of menopause is to prevent estrogen-deprivation and slow the aging process.
   The main factor signaling estrogen deprivation is age. Start observing for early sign of ovary failure and get baseline test at age 40. The early sign is irregular ovulation. A woman looking for it should keep diary of dates of menstrual flow starts, the number of days it continues and observe for cramp and heavy flow. Typical ovulation menstrual flow is regular and predictable, and always the same, not heavy, and it lasts not longer than 5 days. Anovulation (absence of ovulation in a cycle) signals by menses coming less predictably being heavier or lighter and longer and having more cramps. Basal body temperature will document ovulation or its lack.
 The change of pattern that signals the start of anovulation cycles should also signal one to start annual blood tests for E2 (More frequently once it starts dropping).
   At age 40, a woman interested in HT should get health checkup of important organ on which hormone therapy may impact. Complete breast examination with risk factor history by experienced physician. Evaluate cardiovascular system by BP and HR and basic cardiology check. Upper and lower GI tract scope viewing should be accomplished. MRI brain scan should be done. Gyn pelvic evaluation should include, bimanual exam with digital rectal, speculum exam with Pap smear, pre-menstrual endometrium biopsy, abdominal-vaginal ultrasound to evaluate ovaries for cyst or tumor. Any question of ovary abnormality should be followed up by laparoscopy in abdominal cavity. Blood test should include CBC, blood lipid profile, liver function, renal function and hormone (thyroid, ovarian, FSH and LH, parathyroid hormone, cortisol). Most important is supervision by a knowledgeable M.D. who will read this section.
   Once decision is made, the signal to start HT is E2 dropping. It ought to be monitored yearly from age 40 or whenever hot flash starts. When E2 falls to 20 or less pg/ml or FSH>15 units/ml, HT should be considered for starting. (These are approximations; in actual case you, the woman, decide with your experienced physician based on the mix of the blood tests and clinical symptoms of the climacteric)
   What is best medication and delivery route for HT? The Blood test aim of HT in my opinion should be to keep FSH <15 and E2 in range of 30-80 pg/ml. I prefer oral medication because I find it gives the most predictable blood level response of E2 and, more importantly, the dose can be more easily leveraged when given by mouth than it can when given by skin patch or injection. I prefer conjugated equine estrogens (CEE or Premarin) 0.625 mg, or as explained later 0.3125, taken day-1 to day-25 of menstrual cycle. (If no menses, it is started 1st day of each calendar month and discontinued after 25th day) A bleeding usually occurs in the few days off CEE, but, regardless, the CEE pill is started calendar day-1 of subsequent month. The progesterone medication Provera (medroxy-progesterone acetate) 2.5 mg, or 1.25 mg, is added to the cyclic regimen day-16 to -25 to regularize menstruation and also to provide an anti-growth affect on Premarin’s proliferative stimulus and thus lower its cancer risk.
   How long to continue this regimen and in what dose is an experimental question. It should be stopped because of complication or illness. It needs to be monitored by yearly health check and blood test. The doses are the result of my experience in HRT. The ideal is to give the lowest dose of estrogens that will keep the E2 and FSH & LH at levels, as one would expect for an age 40s pre-menopause woman. Similarly with Provera at 1.25 or 0.625 mg dose or as low as is judged best to keep menses regular and not heavy. Doses of 1.25 or 2.5 mg CEE, or Premarin, have been used in HRT, but that is too much and will increase complication rate. Presently I am advising starting at 0.625 CEE. Some women may thrive and have good E2 and FSH levels on CEE 0.3125 mg (next lowest tablet or half cut 0.625 tab).
The risks are cancers of breasts or uterus, and cardiovascular problem due to internal blood clot. In my opinion, with proper check up and attention to detail they are each acceptable risks considering the benefit of HRT in delaying aging and promoting energetic good health.

I feel that HRT remains an experimental therapy whose risks need to be balanced against the hoped for benefits of assisting healthy longevity. And I am tending to prefer the reduced dose of CEE (0.3125 mg a day) and, with Provera lesser duration (1 week) and lower dose (1.25  or 0.625 mg).
   The search for Healthy Longevity involves personal risk but in my opinion Hormone Therapy in women is worth the risk. (But we need to continue to clarify it)

Endnote: Popular HT today is frequently adding male hormone testosterone by skin patch with the idea it will increase female sexual lust and its enjoyment. In my opinion the aim of healthy longevity is not to make lust; it is to live longer, healthier. The male hormone adds to cardiovascular, liver and cancer risk.
     END OF CHAPTER. To read next now, click 8.24 Male "Menopause" - Hormone Replacement?

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