Perimenopause is a time of “Endogenous Ovarian Hyperstimulation”by Dr. Jerilynn C. Prior, Scientific Director, Centre for Menstrual Cycle and Ovulation Research
“Perimenopausal endogenous ovarian hyper-stimulation” is the exact opposite of “The Myth of the Shriveling Ovary”: High estrogen levels during perimenopause, coupled with characteristically intermittent ovulation, can explain much of the misery of perimenopause.
My hypothesis is based on the assumption that inhibin production decreases while there are still viable follicles (capable of producing both estrogen and eggs) in the ovaries and that this in turn stimulates FSH to increase the production of estrogen in the follicles. I offer five pieces of evidence for this hypothesis:
Perimenopausal changes are similar to changes caused by some infertility treatments.
In vitro fertilization (IVF) requires laparoscopic surgery (through a small tube in the abdomen) to suck up ovarian egg cells that are nearly ready to ovulate so they can be grown and fertilized in a laboratory and then injected into the woman’s uterus. In order to collect the maximum number of eggs, gynecologists override inhibin using a technique called “ovarian hyper-stimulation.” The woman is given daily injections of FSH until many follicles have been stimulated and estrogen levels are very high. She is then injected with another hormone (much like luteinizing hormone [LH], another pituitary hormone that stimulates the ovary) to mimic the normal mid-cycle LH surge and this triggers ovulation.
A rare pituitary tumor causes higher-than-normal FSH levels, resulting in hormone levels and symptoms similar to those experienced in menopause.
In an “experiment of nature,” a 36-year-old woman with a tumor on her pituitary gland complained of very heavy menstrual flow. An ultrasound of her pelvis showed seven ovarian cysts and an unusually thick endometrium (lining of the uterus). Her bleeding was successfully treated with medroxyprogesterone (Provera) for ten days each month. This woman’s FSH levels were increased, but only to a level commonly found in perimenopausal woman during the five or more years before the last menstrual period. Her inhibin level was in the normal range, but her estrogen levels during days four to eight of her cycle, were about 12 times higher than normal for the early follicular phase.
More ovarian follicles are used up each year during a woman’s late 30s and early 40s, as compared to earlier in her life.
Pathologists have observed that there is a steady decrease in the numbers of ovarian follicles as women age. (The highest number of follicles is present before birth). This gradual loss takes place during adolescence and young adulthood without any perceptible influence of FSH. The marked increase in the rate of decline in midlife is an indication that more follicles are being stimulated.
Women in their forties are more likely than younger women to be pregnant with non-identical twins (i.e. from two different eggs).
Many women try unsuccessfully to get pregnant for years and then are suddenly successful: compared to younger mothers, these women in their 40s are more likely to bear non-identical twins. In these cases, two ovarian follicles are stimulated, both ovulate and both are fertilized. This could well be due to lower levels of inhibin and higher FSH levels.
Average estrogen levels in perimenopausal women are higher than in younger women.
Although perimenopausal women often believe their estrogen levels to be high, scientists have been slow to acknowledge this possibility. However, two recent studies may change this. One study (subtitled “hyperestrogenism in the perimenopause”) compared the amounts of estrogen (estrone in urine, during one cycle) in two groups of regularly cycling women—one group aged 47 or over and another aged 19 to 38. Ovulation occurred in some cycles and not in others. The older women not only had higher levels of estrogen but also had lower levels of progesterone.
Another study involved a large, randomly selected group of women aged 45 to 55 in Melbourne, Australia. During the early follicular phase, these women showed unexpectedly high estrogen levels (averaging 226 pmol/L) as compared to the expected average of 175 pmol/L. Forty-two per cent of women in a subgroup who had skipped periods for three to 11 months, had levels higher than normal for that phase of their cycle and eight per cent had levels higher than the usual mid-cycle estrogen peak.
[I was gratified to find that high estrogen levels during the perimenopause had been found in a large, well-designed study. However, when I read the authors conclusion that the menopausal transition was characterized by “an increase in serum FSH and decrease in estrogen,” I felt I had to write. The authors subsequently acknowledged that I was probably right about high estrogen levels in the perimenopause.]
Women’s experience and “perimenopausal ovarian hyper-stimulation”
In the book Women of the 14th Moon, nurse practitioner Maura Kelsea says, “At [peri]menopause* life can turn into one long premenstrual experience. Hormones slap you up against the doors of your unfinished business.” Her description of “one long premenstrual experience” aptly describes the physical and emotional upset related to abnormally high estrogen levels. If a woman is to differentiate between moods caused by the social stress of the menopausal transition, and moods caused by high estrogen levels, it helps to be able to recognize the effects of abnormally high estrogen.
For women who menstruate, there are two accurate signs of high estrogen levels that normally occur for a day or two at the middle of a menstrual cycle: front-of the-breast tenderness and stretchy cervical mucus. If estrogen remains high for several days, then the breasts also swell, become firmer and may develop the kind of tenderness often characteristic of early pregnancy. Stretchy mucus is caused by estrogen stimulation of the glands of the cervix (the mouth of the uterus). This mucus is clear and slippery (like raw egg white), can be stretched in a long thread 5-7 cm (2-3" long) and acts to assist sperm traveling into the uterus to fertilize an egg. This type of mucus disappears after mid-cycle when progesterone comes on the scene. Therefore, not only is mucus a sign of high estrogen levels, its disappearance is good evidence of ovulation.
Many perimenopausal women have a high estrogen mid-cycle peak without ovulation. FSH then stimulates another follicle to make high estrogen levels that peak a week or so later. At that point the endometrium has become thickened, is over stimulated and begins to bleed. Thus a common menstrual pattern in the perimenopause is for front-of-the-breast tenderness and stretchy mucus to begin in the middle of the cycle, but then to continue and be at their maximum at the start of a period. Menstrual blood mixed with this mucus may resemble currant jelly. When these signs are present, it is clear evidence that ovulation did not occur. It may also be associated with heavy flow, increased premenstrual moodiness, fluid retention, bloating, and sometimes with menstrual cramps.
What is the significance of these high estrogen levels – aside from breast tenderness and stretchy mucus? According to one recent study, estrogen serves to amplify our body’s hormonal responses to any kind of stress. This was demonstrated by randomizing young men to wear either a high-dose estrogen or a placebo patch and then subjecting all of them to a standard stress test (speaking and doing math problems in front of an audience). Those who were receiving estrogen were found to produce higher levels of the kinds of hormones manufactured in response to stress (i.e. ACTH, cortisol and norepinephrine).
Daytime hot flashes and night sweats are usually interpreted as indicators of low estrogen, despite the fact that they occur in response to rapidly decreasing estrogen levels. Many women who experience flashes find that they start while they are still menstruating regularly – before estrogen could be low. There is now good evidence that hot flashes are related to at least two conditions:
- The brain must have been exposed to high estrogen levels at some time, and
- The level of estrogen has to be decreasing. The brains of women who have regular periods and mid-cycle estrogen surges will become used to high estrogen levels.
When estrogen decreases –even from high to normal—hot flushes are triggered. Two studies have now shown that severe hot flushes can occur concurrently with either very high or normal estrogen levels.
Treating “perimenopausal endogenous ovarian hyperstimulation”
This picture of erratic (and explosive) estrogen levels in perimenopause not only can help us to make sense of our experiences. It can also guide us toward appropriate treatment choices, including the avoidance of supplementary estrogen until flow has been gone for a year and the possible use of cyclic progesterone.
In the normal course of events a 47-year-old woman seeing her doctor about night sweats, heavy flow and PMS would likely be given combined hormone (estrogen/progestin) therapy or the oral contraceptive pill. (She might even be told that she is too young to be menopausal and scheduled for a D & C). She is not likely to be told that there are many things she could do to help herself. She could find and talk to other women who have come through the perimenopause; she could get more information about perimenopause at community seminars and read about perimenopause. She could also help herself by exercising regularly. Walking (or more strenuous exercise) for 30 minutes a day may not alleviate all premenstrual symptoms but will help reduce stress, control weight, allow more sound sleep, possibly relieve hot flushes and be good for both bones and heart. The hot flushes can also be helped by a daily dose of vitamin E (400-800 IU) and even more so, by relaxation training. Finally, she could use vitamin B6, oil of evening primrose and herbal remedies like black cohosh to see if they help.
If perimenopause is a time of high estrogen and low progesterone, a logical treatment is supplementary natural oral micronized progesterone or medroxyprogesterone, provided that the progesterone and/or progestin produce adequate physiological blood levels to be effective. At the outset, progestin/progesterone may briefly (for one cycle) exacerbate estrogen-related mood symptoms, migraines or breast tenderness. But if you persist, progesterone will block these unpleasant symptoms.
Progestin/progesterone therapy is certainly indicated when estrogen excess (relative to progesterone) causes spotting, heavy flow (defined as more than 16 soaked pads/tampons a period), periods too close together (e.g. two periods within the same month) or endometrial hyperplasia (over-stimulation of the cells lining the uterus). These situations are so common in the perimenopause that physicians or nurse practitioners should feel comfortable prescribing this therapy; gynecological consultation is rarely necessary and endometrial biopsies or ultrasounds are usually not needed. The treatment involves either oral micronized progesterone (Prometrium® in a dose of 300 mg at bedtime because of its drowsy side-effect, or medroxyprogesterone acetate (MPA) in a dose of 10 mg per day for 16 days – on days 12 to 27, counting from the first day of the menstrual period. This will usually bring flow back to normal.
To ensure an adequate counterbalance to the high estrogen, each 16-day course of progestin/progesterone must be completed, even if bleeding starts. In other words, the woman should finish the 16 days but – at the same time – start counting towards day 12 and the next dose from the beginning of flow. This means that during some cycles, she may be off progesterone for only a few days. Cyclic progesterone therapy should be continued for at least six months.
In some situations, if excess estrogen symptoms are severe, if flow starts before the ninth day of the progestin/progesterone therapy, or if breakthrough bleeding occurs, higher doses of progesterone may be needed. For instance, I have used cyclic natural progesterone (300 mg per day for days 12 to 27 of the cycle) and added daily progestin (Provera®) at 5 or 10 mg per day every day. The daily dose of progestin can be stopped when flow becomes scant or some periods are skipped, but the progestin/progesterone taken on days 12 to 27 should be continued for another six months.
We know that several old controlled studies showed that hot flushes were relieved by progestin treatments. So the cyclic progestin/progesterone treatment I recommend will not only control heavy bleeding, but also alleviate night sweats that often begin before flow. We also know that in premenopausal women experiencing abnormal cycles, ten days a month of Provera can increase spinal bone density by a high significant 2 per cent. Best of all is the knowledge that cyclic progestin/ progesterone therapy can bring estrogen and progesterone back into a healthy balance. You can monitor your feelings and bodily changes, as well as therapy, using a Daily Perimenopause Diary®.
By dispensing with “The Myth of the Shriveling Ovary” and learning the secrets of “perimenopausal endogenous ovarian hyperstimulation,” we can make sense of the chaotic physical and emotional changes of perimenopause.
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