Στην αρχή ενός φυσιολογικού γεννητικού κύκλου :
εκκρίνεται από τον υποθάλαμο η ορμόνη GnRH, η οποία διεγείρει έναν άλλο αδένα – την υπόφυση -
για να παραχθούν η θυλακιοτρόπος ορμόνη (FSH) και η ωχρινοποιητική ορμόνη (LH). Η FSH προάγει την
ανάπτυξη των ωοθυλακίων και η LH είναι υπεύθυνη για την τελική ωρίμανση και την ωοθυλακιορρηξία
Σε κάθε φυσικό κύκλο, υπό την επίδραση της FSH, αρχίζουν να αναπτύσσονται 8-
12 ωοθυλάκια. Ένα από τα ωοθυλάκια αυτά επικρατεί, μεγαλώνει πιο γρήγορα από τα
άλλα και ονομάζεται «κυρίαρχο» ωοθυλάκιο. Είναι αυτό που θα φθάσει σε τελική
Τα υπόλοιπα ωοθυλάκια θα γίνουν «άτρητα», δηλαδή θα εκφυλιστούν με το
μηχανισμό της ατρησίας. Με τη δράση της LH στο κυρίαρχο ωοθυλάκιο θα επιτευχθεί
ωοθυλακιορρηξία και θα ελευθερωθεί το «ώριμο» ωάριο.
Όσο αναπτύσσεται το ωοθυλάκιο, παράγει την ορμόνη
οιστραδιόλη (Ε 2 ) η οποία επιδρά στον βλεννογόνο της
μήτρας (ενδομήτριο) αυξάνοντας το πάχος του.
Τα υψηλά επίπεδα της οιστραδιόλης προκαλούν την έκκριση
της ορμόνης LH. Η απότομη αυτή αύξηση (αιχμή) της LH
αποτελεί το βιολογικό σήμα για την τελική ωρίμανση του
ωαρίου και την απελευθέρωσή του (ωοθυλακιορρηξία).
Αυτή η φάση του γεννητικού κύκλου αντιπροσωπεύει
τις γόνιμες ημέρες. Μετά την ωοθυλακιορρηξία, το
ωοθυλάκιο μετατρέπεται σε ωχρό σωμάτιο, το οποίο παράγει
κυρίως την ορμόνη προγεστερόνη. Η προγεστερόνη σε
συνδυασμό με τα οιστρογόνα (οιστραδιόλη) προετοιμάζουν
το ενδομήτριο για να δεχθεί και να θρέψει το έμβρυο.
Η διαδικασία της φυσιολογικής σύλληψης
Η ανθρώπινη αναπαραγωγή είναι αποτέλεσμα της ένωσης του
σπερματοζωαρίου με το ωάριο. Τα ωάρια παράγονται από τις ωοθήκες και τα
σπερματοζωάρια από τους όρχεις.
Από την ένωση τους θα Τα σπερματοζωάρια ξεκινούν τη διαδρομή τους
προκύψει το έμβρυο που θα από το έξω τραχηλικό στόμιο, που αποτελεί την πύλη
αναπτυχθεί στη μήτρα για να του έσω γεννητικού συστήματος της γυναίκας, ανοικτή
γεννηθεί το παιδί.
κατά τις λίγες γόνιμες ημέρες, και πορεύονται δια μέσου
Εάν υπάρξει σεξουαλική επαφή τις
γόνιμες ημέρες, το σπέρμα του αυλού του τραχήλου και της κοιλότητας της μήτρας
εναποτίθεται στον κόλπο. προς τις σάλπιγγες.
Η ΣΆΛΠΙΓΓΑ ΠΑΡΑΛΑΜΒΆΝΕΙ ΜΕ ΤΗ ΒΟΉΘΕΙΑ ΤΩΝ ΚΡΟΣΣΏΝ, ΤΟΥ ΑΚΡΑΊΟΥ ΤΜΉΜΑΤΌΣ ΤΗΣ, ΤΟ
ΩΆΡΙΟ ΤΟ ΟΠΟΊΟ ΠΡΌΣΦΑΤΑ ΑΠΕΛΕΥΘΕΡΏΘΗΚΕ ΜΕ ΤΗΝ ΩΟΘΥΛΑΚΙΟΡΡΗΞΊΑ.
Στη σάλπιγγα θα γίνει η γονιμοποίηση του ωαρίου από ένα μόνο σπερματοζωάριο. Το γονιμοποιημένο
ωάριο (ζυγώτης) παραμένει στη σάλπιγγα για τις επόμενες 5-6 ημέρες όπου και διαιρείται σε 2,4,8,16
κ.ο.κ. κύτταρα, καθώς η σάλπιγγα το καθοδηγεί προς την κοιλότητα της μήτρας.
Στη συνέχεια, με τη μορφή της βλαστοκύστης (που απαρτίζεται από 60-120 περίπου κύτταρα) το έμβρυο
μεταναστεύει στην κοιλότητα της μήτρας, εμφυτεύεται στο ενδομήτριο («σύλληψη») και συνεχίζει την ανάπτυξή του.
Οι απαραίτητες προϋποθέσεις που πρέπει να συντρέχουν ταυτόχρονα, προκειμένου να επιτευχθεί
φυσιολογική σύλληψη είναι:
Oι σάλπιγγες να είναι διαβατές και λειτουργικές για να παραλάβουν το ωάριο από την σύστοιχη ωοθήκη και να
επιτρέψουν στα σπερματοζωάρια να συναντήσουν το ωάριο.
Tο σπέρμα να έχει φυσιολογικές παραμέτρους, δηλαδή τα σπερματοζωάρια να έχουν ικανοποιητικό αριθμό,καλή προωθητική
κινητικότητα και ζωτικότητα για να μπορέσουν μερικά απ' αυτά να φθάσουν στο ωάριο παρακάμπτοντας τα εμπόδια.
Η δίοδος των σπερματοζωαρίων από τον κόλπο μέχρι τις σάλπιγγες (ωαγωγούς) να είναι ευχερής, με
φιλικό κυρίως το περιβάλλον της τραχηλικής βλέννας.
Nα γίνεται ωοθυλακιορρηξία με αποτέλεσμα
την απελευθέρωση από το ωοθυλάκιο
Nα υπάρχει σεξουαλική επαφή στις γόνιμες ημέρες.
Είναι γνωστό ότι:
Η ενδομητρίωση μειώνει τη γονιμότητα σε μεγάλο ποσοστό.
Σε ένα ποσοστό 25- 30% η υπογονιμότητα χαρακτηρίζεται ανεξήγητη.
reference range (FSH)
1-11 females; follicular and luteal phase
6-26 at ovulation
Note that reference ranges may vary between laboratories.
Female Hormone Levels
Hormone to Test What Value Means
to Test Values
Follicle Stimulating Day 3 3-20
Hormone ( FSH ) mIU/ml FSH is often used as a gauge of ovarian reserve. In general, under 6 is excellent, 6-9 is good, 9-10
fair, 10-13 diminished reserve, 13+ very hard to stimulate. In PCOS testing, the LH:FSH ratio may be used
in the diagnosis. The ratio is usually close to 1:1, but if the LH is higher, it is one possible indication of
Estradiol (E2) Day 3 25-75
pg/ml Levels on the lower end tend to be better for stimulating. Abnormally high levels on day 3 may
indicate existence of a functional cyst or diminished ovarian reserve.
Estradiol (E2) Day 4-5 of 100+
meds pg/ml There are no charts showing E2 levels during stimulation since there is a wide variation depending
or 2x on how many follicles are being produced and their size. Most doctors will consider any increase in E2 a
Day 3 positive sign, but others use a formula of either 100 pg/ml after 4 days of stims, or a doubling in E2 from
the level taken on cycle day 3.
Estradiol (E2) Surge/hCG 200 +
day pg/ml The levels should be 200-600 per mature (18 mm) follicle. These levels are sometimes lower in
Luteinizing Hormone Day 3 <7
( LH) mIU/ml A normal LH level is similar to FSH. An LH that is higher than FSH is one indication of PCOS.
Luteinizing Hormone Surge Day > 20
( LH) mIU/ml The LH surge leads to ovulation within 48 hours.
Prolactin Day 3 < 24
ng/ml Increased prolactin levels can interfere with ovulation. They may also indicate further testing (MRI)
should be done to check for a pituitary tumor. Some women with PCOS also have hyperprolactinemia.
Progesterone (P4) Day 3 < 1.5
ng/ml Often called the follicular phase level. An elevated level may indicate a lower pregnancy rate. If low
progesterone levels are an issue for you, consider taking a natural fertility supplement like FertilAid for
Progesterone (P4) 7 dpo > 15
ng/ml A progesterone test is done to confirm ovulation. When a follicle releases its egg, it becomes what
is called a corpus luteum and produces progesterone. A level over 5 probably indicates some form of
ovulation, but most doctors want to see a level over 10 on a natural cycle, and a level over 15 on a
medicated cycle. There is no mid-luteal level that predicts pregnancy. Some say the test may be more
accurate if done first thing in the morning after fasting.
Thyroid Stimulating Day 3 .4-4
Hormone (TSH) uIU/ml Mid-range normal in most labs is about 1.7. A high level of TSH combined with a low or normal T4
level generally indicates hypothyroidism, which can have an effect on fertility.
Free Triiodothyronine Day 3 1.4-4.4
(T3) pg/ml Sometimes the diseased thyroid gland will start producing very high levels of T3 but still produce
normal levels of T4. Therefore measurement of both hormones provides an even more accurate evaluation
of thyroid function.
Free Thyroxine (T4) Day 3 .8-2
ng/dl A low level may indicate a diseased thyroid gland or may indicate a non- functioning pituitary gland
which is not stimulating the thyroid to produce T4. If the T4 is low and the TSH is normal, that is more
likely to indicate a problem with the pituitary.
Total Testosterone Day 3 6-86
ng/dl Testosterone is secreted from the adrenal gland and the ovaries. Most would consider a level above
50 to be somewhat elevated.
Free Testosterone Day 3 .7-3.6
Dehydroepiandrosterone Day 3 35-430
Sulfate (DHEAS) ug/dl An elevated DHEAS level may be improved through use of dexamethasone, prednisone, or insulin-
Androstenedione Day 3 .7-3.1
Sex Hormone Binding Day 3 18-114
Globulin (SHBG) nmol/l Increased androgen production often leads to lower SHBG
17 Hydroxyprogesterone Day 3 20-100
ng/dl Mid-cycle peak would be 100-250 ng/dl, luteal phase 100-500 ng/dl
Fasting Insulin 8-16 hours < 30
fasting mIU/ml The normal range here doesn't give all the information. A fasting insulin of 10-13 generally
indicates some insulin resistance, and levels above 13 indicate greater insulin resistance.
How is it used?
FSH is often used in conjunction
with other tests (LH, FSH levels are used to help determine the reason a man has a low
testosterone , estradiol , and
progesterone ) in the workup of
infertility in both men and
FSH levels are also useful in the investigation of menstrual irregularities and to aid
in the diagnosis of pituitary disorders or diseases involving the ovaries or testes. In children, FSH and LH
are used to diagnose delayed or precocious (early) puberty.
When is it ordered?
In women and men, FSH may be ordered to determine if a woman has reached menopause .
FSH and LH are
Signs of puberty may include:
ordered as part of the
In children, FSH and LH may
workup of infertility and b e o r d e r e d w h e n a b o y o r g i r l breast enlargement in females
pituitary or gonadal does not appear to be entering growth of pubic hair
disorders. puberty at an appropriate age
(either too late or too soon). genitalia growth in males
beginning of menstruation in
If any or some of these signs appear at a younger than average age or are delayed beyond the expected
age range for puberty, it may be an indication of a more serious problem involving the hypothalamus,
pituitary, gonads (ovaries or testes) or other systems.
The measurement of LH and FSH may differentiate between benign symptoms and true disease. Once
it is established that symptoms are a result of true disease, further testing can be done to discern
the underlying cause.
What does the test result mean?
In women, FSH and LH levels can
help to differentiate between
Increased levels of FSH and LH are consistent with primary ovarian failure.
primary ovarian failure (failure of
the ovaries themselves) and Some causes of primary ovarian failure are listed below.
secondary ovarian failure (failure
of the ovaries due to disorders of
either the pituitary or the
Ovarian agenesis (failure to develop ovaries)
Chromosomal abnormality, such as Turner’s syndrome
Ovarian steroidogenesis defect, such as 17 alpha hydroxylase deficiency
Premature ovarian failure due to:
Chronic anovulation (failure to ovulate) due to:
Polycystic ovary syndrome (PCOS)
When a woman enters menopause and her ovaries stop working, FSH levels will rise.
Low levels of FSH and LH are consistent with secondary ovarian failure due to a pituitary or hypothalamic problem.
In men, high FSH levels are due to primary testicular failure. This can be due to developmental defects in
testicular growth or to testicular injury, as indicated below.
Chromosomal abnormality, such as Klinefelters syndrome
Viral infection ( mumps)
Germ cell tumor
Low levels are consistent with pituitary or hypothalamic disorders.
In young children, high levels of FSH and LH and/or development of secondary sexual
characteristics at an unusually young age are an indication of precocious puberty. This is
much more common in girls than in boys. This premature development can have many
different underlying causes that need to be diagnosed and treated. Some of the causes
Central nervous system lesions
Hormone - secreting tumors
Ovarian tumors or cysts
Normal prepubescent levels of LH and FSH in children exhibiting some signs of pubertal changes
may indicate a benign form of precocious puberty with no underlying or discernable cause or may
just be a normal variation of puberty.
In delayed puberty, LH and FSH levels can be normal or below what is expected for a youth within
the age range of puberty. The test for LH response to GnRH may need to be performed along with
other testing to diagnose the reason for the delayed puberty. Some of the causes for delayed
puberty can include:
Gonadal (ovary or testes) failure (such as PCOS)
Turner's syndrome (chromosomal abnormality in girls)
Klinefelter's syndrome (chromosomal abnormality in boys)
Eating disorder (anorexia nervosa)
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AFP AT A GLANCE
Past Issues TONI M. CUTSON, M.D., M.H.S.
Annual Indexes Durham Veterans Affairs Medical Center, Durham, North Carolina
EMILY MEULEMAN, M.S., R.N.C.
CME Quiz University of Michigan Chelsea Family Practice Center, Ann Arbor, Michigan
EBM Toolkit Many women will spend one third of their lifetime after menopause. A growing
About AFP number of options are available for the treatment of menopausal symptoms
Information for like vasomotor instability and vaginal atrophy, as well as the long-term health
Advertisers risks such as cardiovascular disease and osteoporosis that are associated
Subscriptions with menopause. Currently, hormone replacement therapy (estrogen with or
Contact AFP without progestin) is the primary treatment for the symptoms and long-term
risks associated with menopause. However, recent evidence calls into
question the protective effect of estrogen on cardiovascular disease risk. The
association of risk for breast cancer with estrogen replacement therapy also
has not been fully clarified. In addition, many women cannot or choose not to
take hormones. For treatment of osteoporosis and heart disease,
pharmacologic choices include antiresorptive agents such as
bisphosphonates and calcitonin, and estrogens or selective estrogen receptor
modulators such as raloxifene. In addition, complementary options that
include vitamins, herbal treatments, exercise and other lifestyle adaptations
are gaining increased interest. The growing number of choices and questions
in this area emphasizes the need to individualize a treatment plan for each
woman to meet her specific needs. (Am Fam Physician 2000;61:1391-
For nearly 70 percent of women, the transition into menopause is
smooth 1 ; however, many women seek advice for management of
associated symptoms such as hot flushes or vaginal dryness, or for
See editorial assistance in the prevention of associated long-term health problems
such as osteoporosis and coronary artery disease.
on page 1285. Women and physicians have questions and concerns about the use of
hormone replacement therapy (HRT) during and after menopause. In
addition, many alternative and nonhormonal treatments lack rigorous
scientific study but are popular with patients. Family physicians need to know the
available treatment options in order to address patients' questions and concerns.
Pharmacologic Therapy for Symptoms of Menopause
A hot flush is a flushed or blushed feeling of the face, neck and upper chest. Skin
temperature can rise several degrees. The severity of hot flushes increases with fatigue
and stress. The most severe hot flushes usually occur at night and may adversely affect
sleep. About 75 percent of American women experience hot flushes during menopause,
although not all are subjectively troublesome. Menopausal women living in Asian
countries experience a much lower incidence of hot flushes and sleep disturbance,
which may be related to dietary factors such as phytoestrogens that are contained in soy
products. 2 Hot flushes may persist for several years around the time of menopause.
Estrogen therapy can reduce hot flushes.
Progesterone therapy alone may help women who Estrogen therapy can effectively
choose not to take estrogen. Clonidine (Catapres), a treat menopausal symptoms such
centrally acting alpha-adrenergic agonist, has also as vasomotor instability, mood
swings, concentration difficulties,
been used with mixed success.3 dyspareunia and vaginal irritation.
Mood swings, depression and concentration difficulties are psychologic symptoms that
are associated with menopause. Estrogen therapy improves mood and dysphoria,
possibly by affecting the metabolism of serotonin in the central nervous system. 4
However, depression has not been shown to be caused by menopause alone but is
usually the result of additional factors that include previous history of depression,
psychologic factors and life stressors that may accumulate around the time of
menopause. 3 While estrogen improves mood or dysphoria associated with menopause,
HRT is not effective in the treatment of primary depression.
The urogenital tissues are estrogen sensitive. Declining estrogen levels lead to atrophy
of the urogenital tissues and vaginal thinning and shortening, resulting in dyspareunia
and urethral irritation. In addition, urinary tract infections and urinary incontinence may
develop because of tissue thinning, laxity, decreased urethral apposition and alteration
of the vaginal flora.
A meta-analysis of estrogen treatment (oral or intravaginal) for urinary incontinence
revealed a significant improvement in subjective symptoms, but no improvement in
objective measures such as urodynamic testing.5 Intravaginal estrogen administration has
been shown to decrease the number of recurrent urinary tract infections.6 Doses of
estriol 0.5 mg administered intravaginally did not cause a significant rise in plasma
estrogen levels within 24 hours. The risk of endometrial cancer is low with this
Pharmacologic Management of Long-Term Risks
Coronary Artery Disease
Estrogen's physiologic effects, such as arterial vasodilatation, decreased fibrinogen
levels, increased high-density lipoprotein (HDL) cholesterol levels and decreased low-
density lipoprotein (LDL) cholesterol levels, are likely to reduce cardiovascular risk.
Unopposed estrogen offers the most beneficial effect on HDL cholesterol levels;
however, the addition of progestin agents does not negate improvement.7 Oral estrogen
can increase the serum HDL level by 20 to 30 percent and reduce the serum LDL level
by 10 to 15 percent. The effect is comparable to or better than that of a statin drug. 8
Many observational studies have shown that estrogen is associated with a 40 to 50
percent reduction in the risk of heart disease. 9-11 Meta-analyses of these nonrandomized
trials9-11 demonstrated a pooled reduction in relative risk of heart disease of one third in
women who had ever used estrogen.12,13
Conversely, the results of the Heart and
Estrogen/Progestin Replacement Study (HERS), 14 a Although studies have provided
recent randomized, controlled trial, found no benefit conflicting results, hormone
of HRT for secondary prevention of cardiovascular replacement therapy is generally
considered effective primary
events in 2,763 postmenopausal women followed prevention of cardiovascular
over four years. 14 Although the conflicting results disease but may be less effective
illustrate the shortcomings of nonrandomized trials in secondary prevention.
and raise caution, it should be noted that the HERS
participants had established coronary heart disease,
and 25 percent of the women in the active treatment arm dropped out of this study.
Perhaps HRT provides minimal to no benefit in women with established coronary heart
disease but may provide primary prevention in otherwise healthy women.
The protective effect of estrogen against stroke is unclear. The National Health and
Nutrition Examination Survey 15 found an adjusted relative risk of 0.37 (95 percent
confidence interval [CI]; range: 0.14 to 0.92) for fatal stroke in women who had ever
used estrogen. In the Leisure World Study,9 the risk of death from stroke for women
who were taking estrogen was reduced by 20 to 40 percent. Other studies have
illustrated no protection against stroke. 10,16
Critics of HRT studies state that women who take estrogen may be better informed and
healthier than women who choose not to take estrogen. Most studies do not have the
rigorous design of a randomized, controlled trial, which is necessary to ascertain
whether the estrogen or the associated healthier attitudes and practices of the
participants are the major causes of reduced disease. Until such information is
available, HRT is considered important in the primary prevention of cardiovascular
disease; however, questions remain about its role in secondary cardiovascular risk
In the United States, 4 to 6 million women have osteoporosis. One consequence of this
situation is that more than 250,000 hip fractures occur annually, with a health care cost
of approximately $14 billion per year. A hip fracture carries a 10 to 20 percent risk of
death within a year and a 25 percent chance of institutionalization. 17 Estrogen
deficiency is the primary cause of osteoporosis, although many other secondary causes
for osteoporosis exist (e.g., poor diet, glucocorticoid excess). Thus, women at risk for
osteoporosis should be considered candidates for HRT.
The daily dosage required to prevent bone loss is 0.625 mg of conjugated estrogen or
the equivalent (Table 1), but even 0.3 mg may suffice if taken with adequate calcium
supplements. Resumption of bone loss following discontinuation of HRT has been
reported.18 The maximal protective effect of estrogen on bone mineral density (BMD)
occurs if HRT is initiated within three years of menopause. However, effectiveness has
been documented with initiation of therapy in the later years of menopause. 9
Minimum Effective Dosages of Estrogens for Prevention of
Formulation* Minimum effective dosage †
Conjugated 0.625 mg $15
Micronized 1.0 mg 14
Esterified estrogen 0.625 mg
Estropipate 1.25 mg
Transdermal 0.05 mg
Combipatch 0.05 mg estradiol/0.14 mg norethindrone 30
Estratest 1.25 mg esterified estrogen/2.5 mg methyltestosterone 31
Estratest HS 0.625 mg esterified estrogen/1.25 mg methyltestosterone 25
Premphase‡ 0.625 mg conjugated estrogen (14 tablets) and 0.625 mg 20
conjugated estrogen/5 mg medroxyprogesterone acetate (14
tablets in sequence)
Prempro 0.625 mg conjugated estrogen/2.5 mg or 5.0 mg 22
medroxyprogesterone acetate each
Micronized 0.01% or 0.1 mg per g (42.5 g/tube) 36§
Estropipate 1.5 mg per g (42.5 g/tube) 48§
Conjugated 0.625 mg per g (42.5 g/tube) 42
Dienestrol 0.01% or 0.1 mg per g (78 g/tube) 30§
Estradiol 7.5 µg per 24 hours every 90 days 69
*--Not all dosages are available in all brands; available dosages are listed.
†--Estimated cost to the pharmacist based on average wholesale prices (rounded to the
nearest dollar) for one month of therapy at the minimum effective dosage in Red book.
Montvale, N.J.: Medical Economics Data, 1999. Cost to the patient will be greater,
depending on prescription filling fee.
‡--Two separate tablets in monthly pack. Estrogen-only tablet for first 14 days of the
month. Combination tablet for the next 14 days.
§--Price per tube.
Study results demonstrate the efficacy of estrogen in increasing BMD and decreasing
the number of fractures of the forearm, vertebrae and hip.19,20 Thus, HRT is not only
preventive but can also be used to treat established osteoporosis. Spinal BMD has been
shown to increase by 10.6 percent 12 and hip BMD by 5.5 percent over a two-year
period with HRT. The relative risk of hip fracture was 0.65 (95 percent CI; range: 0.44
to 0.98) in women who had taken estrogen at any time and 0.32 (95 percent CI; range:
0.12 to 0.98) in those taking estrogen within the past two years. 21 In one large study,
the incidence of all osteoporotic fractures was estimated to be reduced by 30 to 50
percent with long-term HRT (three to 10 years' duration).22
Alternatives to HRT include bisphosphonates, which inhibit osteoclast activity and
localize and bind to resorption sites on the bone. The current recommended therapeutic
course is three years, to avoid the potential risk of osteomalacia. Long-term data are
forthcoming. Alendronate (Fosamax) is labeled by the U.S. Food and Drug
Administration for treatment of osteoporosis. Several large, randomized, controlled
trials have demonstrated its efficacy in increasing BMD and reducing fractures by 40
percent.23,24 To prevent esophagitis, alendronate should be taken in an upright position
with a full glass of water 30 minutes before eating; the upright position should be
maintained for the 30 minutes. This agent may cause musculoskeletal pain and
gastrointestinal upset. Contraindications include symptomatic upper gastrointestinal
disease (esophageal stricture, achalasia, gastroesophageal reflux) and renal
Etidronate (Didronel) is another bisphosphonate. It is FDA-labeled for treatment of
Paget's disease, but has had an unlabeled use as a treatment for osteoporosis in patients
who cannot tolerate alendronate. In one study, 25 it was documented in a sample of 66
women with postmenopausal osteoporosis that etidronate increased vertebral BMD 5.3
percent (95 percent CI; range: 2.0 to 8.6) and reduced fracture rate (six versus 54
fractures per 100 patient years) over three years. The patients in the intervention arm
received etidronate in a dosage of 400 mg per day for two weeks every 15 weeks for
three years. This agent has proved effective in increasing vertebral BMD and reducing
fracture rates. It is more cost effective than alendronate.22
Intranasal calcitonin (Mialcalcin) is a polypeptide hormone that also inhibits
osteoclastic activity. An injectable form has been available for about 15 years; however,
a convenient intranasal form is now available for treatment of established osteoporosis.
In a randomized, placebo-controlled trial, 76 percent of postmenopausal women
receiving a dosage of 200 IU per day intranasally demonstrated a positive response,
with a 2.0 to 3.6 percent increase in BMD, while participants receiving placebo lost
bone mass.26,27 No data are available on change in fracture rate.
A new selective estrogen receptor modulator,
raloxifene (Evista), has been FDA-labeled for Agents that have been proved to
prophylactic treatment of osteoporosis. For women increase bone mineral density in
whose main interest is prevention of osteoporosis, menopausal women include
estrogen, alendronate, etidronate,
this agent offers an alternative to traditional HRT. calcitonin and raloxifene.
The modulator does not stimulate endometrial or
breast tissue but does increase BMD (although only
approximately one half as effectively as estrogen) and reduce total and LDL cholesterol
levels with no change in triglycerides or HDL cholesterol levels.28 Longitudinal studies
are needed to determine the net effect on cardiovascular disease and breast cancer.
Other selective estrogen receptor modulators pending FDA labeling include droloxifene
The evidence concerning prevention of dementia with HRT is conflicting but
promising. Observational studies have demonstrated a protective effect and no effect on
the risk of Alzheimer's dementia. A meta-analysis of the observational studies of
estrogen use and development of dementia have shown an odds ratio of 0.71 (95
percent CI; range: 0.52 to 0.98).29 Prospective randomized trials are needed. Proposed
mechanisms of action include increased blood flow to the brain and enhanced neuronal
dendritic growth to support neurotransmitter production.
The mortality rate among women who take estrogen has been shown to be lower than
the rate in women who do not. The Nurses Health Study 16 (data from 1976 to 1994)
revealed decreased mortality in women who took estrogen; however, the benefit
decreased with longer duration of use and was lower in women already considered at
low risk for coronary artery disease. Other studies have shown lower all-cause
mortality rates among women taking HRT.30
The issue of HRT among special populations of women (i.e., survivors of breast cancer)
has not been adequately addressed. Trials are currently under way to address this issue.
HRT Administration and Regimens
The most common HRT regimen consists of estrogen with or without progestin.
Transdermal estrogen preparations avoid the first-pass liver effect. This may be
efficacious in the treatment of vasomotor symptoms but may also reduce the positive
effect on cholesterol levels. Many women have a problem with skin sensitivity to the
patches. Vaginal preparations are widely used, especially for treatment of atrophic
vaginitis. Injectable and slow-release implant formulations of estrogen are available but
are not preferred by many patients. Despite the availability of a variety of
administration routes, the concern about coronary artery disease makes the oral route of
administration preferable because of the hepatic effect on HDL cholesterol levels.
Estrogen-only regimens are appropriate in women who have undergone hysterectomy.
The paucity of data showing that progestins protect against an increased risk of breast
cancer and the concern regarding the adverse effect of progestins on lipoproteins make
the estrogen-only regimen preferable to combined therapy in women without a uterus.
Progestin should be added to the estrogen-only regimen for at least 12 days per month
in women with an intact uterus to avoid the five- to eightfold risk of endometrial
adenocarcinoma resulting from unopposed estrogen use. If progestins are not tolerated,
women who have not had a hysterectomy may be followed closely on an estrogen-only
regimen with an annual endometrial biopsy, uterine ultrasonography or progesterone
challenges, 31 to screen for endometrial hyperplasia.
Postmenopausal women generally dislike cyclic regimens because they mean
resumption of menses. Continuous regimens are the most widely accepted. Oral pill
(singly or in combination) and combination skin patch (Combipatch) formulations are
available. Vaginal bleeding may occur during the first six months of therapy; however,
amenorrhea is usually achieved after the first year. Some authors recommend that
patients undergo a pretreatment endometrial biopsy to exclude hyperplasia before
initiating hormone therapy; others believe this is unnecessary in asymptomatic women
and recommend biopsy only if bleeding persists past six months of therapy.32
The Role of Androgens/Testosterone
Interest is growing in the use of androgens to enhance well-being during
Androgenic hormones are produced in the ovaries and the adrenal glands and act on
musculoskeletal, nervous, hepatic and vascular tissues. Androgens are known to
increase libido and protect bone mass.33,34 However, lipid profiles change when
androgens are added to HRT. The HDL fraction decreases with androgen therapy;
however, triglyceride concentrations decrease significantly in patients given estrogen-
androgen combination therapy. HDL cholesterol and triglyceride levels may be
important factors in determining cardiac risk. 34
Adverse effects such as virilization are few and
can be minimized with reduction of the dosage.
Considering the subsequent lipid effect
(although without information from long-term TABLE 2
studies), it is probably prudent to avoid
androgen therapy in women with known low
HDL cholesterol levels and established
Relative and Absolute
cardiovascular disease. 34
Adverse Effects Hormone Replacement
Forty percent of women discontinue HRT Therapy
within eight months of initial therapy or never
fill the prescription. 35 Adverse effects attributed
to HRT include breast tenderness, breakthrough
bleeding, cancer (breast or endometrial) and contraindications contraindications
thromboembolic disorders. In addition, there are
relative and absolute contraindications to the
use of HRT (Table 2).35,36 The Nurses' Health Estrogen- Chronic liver
Study 38 reported that risk of breast cancer was responsive breast
highest among women who received HRT for
five years or longer (relative risk: 1.45; 95 disease
percent CI; range: 1.01 to 2.09). No elevated cancer
risk associated with past use was reported. A
collaborative analysis of 51 studies showed an Severe
increased risk with duration of therapy (relative Endometrial
risk: 1.35; P = 0.0001), although the excess
numbers of breast cancers were small. 39 A hypertriglyceridemia
definitive answer has not emerged from the cancer
large number of studies, suggesting that the risk
of breast cancer is relatively low. Randomized,
controlled trials are needed, and the Women's
Health Initiative may provide more answers. Endometriosis
Many herbal substances and similar products thromboembolic
have been suggested as therapeutic agents in
managing menopause, but most lack scientific Active
proof of efficacy. disease
Natural progesterone, present in yam root, is
touted as a remedy for premenstrual and disease
menopausal symptoms. The natural ingredient,
disogenin, is not well absorbed orally, and
special compounding into a topical cream is History of
necessary. The standard dosage is 40 to 1,000
mg per day of the 1.5 or 3.0 percent topical
Information from Grady D, Rubin SM,
formulation, applied twice daily to areas with Petitti DB, Fox CS, Black D, Ettinger B,
soft tissue (e.g., abdomen, inner thighs). It is et al. Hormone therapy to prevent
also available in an oral micronized form, disease and prolong life in
Prometrium, and considered to have no adverse postmenopausal women. Ann Intern
Med 1992;117:1016-37, and Reuben
side effects at standard doses. 40,41 DB, ed. Geriatric review syllabus A
core curriculum in geriatric medicine.
Soy products contain compounds known as 3rd ed. New York: AGS, 1996.
isoflavones (natural phytoestrogens), which are
500 to 1,000 times weaker than endogenous
estrogen. Soy protein appears to be effective in reducing hot flushes, bone loss and
total and LDL cholesterol levels. It may also inhibit the growth of different cancer cell
lines in vitro and in vivo. 42 Food sources include soy nuts, soy milk and tofu.
Several other natural substances have been used to treat menopausal symptoms. These
substances include vitamin E, which is thought to stabilize estrogen levels; black
cohosh (Cimicifuga racemosa), marketed in the United States as Remifemin (standard
dosage: 40 mg per day), thought to suppress luteinizing hormone; and Chasteberry
(Vitex agnus-castus), which may decrease prolactin. None of these products has been
examined or has proved effective in well-designed clinical trials. Other substances, such
as dong quai (Angelica sinensis) and licorice root (Glycyrrhiza glabra) are not
considered helpful. No herbal derivative has been shown to be effective in the
prevention or treatment of osteoporosis.43
Adequate dietary calcium intake is essential, and supplementation is helpful if dietary
sources are inadequate. Total calcium intake should approximate 1,500 mg per day,
which usually requires supplementation.
Mounting evidence suggests that vitamin D deficiency may be more prevalent than
previously believed. Vitamin D supplementation (400 to 800 IU per day), in addition to
calcium supplementation, is recommended for women who cannot spend 30 minutes per
day in the sun.44
Several lifestyle approaches may be recommended for the management of menopausal
symptoms in general (Table 3). Most are common-sense recommendations that apply to
a healthy lifestyle.
Lifestyle Approaches for Wellness in Menopause
High fiber Decreases CAD risk
Low fat Improves cholesterol profile
Rich in May decrease hot flushes and other menopausal symptoms
intake of soy
Decreases CAD risk
Weight- Improves cholesterol profile
Strengthening Decreases osteoporosis risk, decreases risk of falls, may decrease hot
flushes, may improve depressive symptoms, aids sleep, helps prevent
Smoking Decreases CAD risk, decreases osteoporosis risk, may decrease hot
Decrease May decrease hot flushes, decreases osteoporosis risk
Maintain May decrease vaginal dryness, may improve depressive symptoms
Daily sunlight May improve depressive symptoms, decreases osteoporosis risk
Relaxation and Decreases CAD risk, may improve depressive symptoms
CAD = coronary artery disease.
A woman's current health status, personal health risks and beliefs should guide the
management of symptoms and health risks related to menopause. The goals of therapy
and the risks and benefits of the various treatment options should be presented and
discussed. On average, the incidence of heart disease far outpaces the risk of breast
cancer (a 1 in 2 versus 1 in 8 chance, respectively); but clearly, the fear of breast
cancer emerges as a more powerful influence in the decision-making process for many
women. Although breast cancer may claim 43,000 lives per year, coronary artery
disease claims 223,000 lives and hip fractures claim 65,000 lives annually. 45
In a model to assess the impact of HRT on life expectancy based on the risks of
coronary artery disease, hip fracture and breast cancer, the benefit of HRT outweighed
the risk of breast cancer in nearly all women. However, long-term HRT was not
recommended for women at low risk for coronary artery disease or at high risk for
breast cancer.45 Despite the HERS results showing no benefit from HRT in secondary
prevention of cardiovascular disease, the recommendation of HRT for primary
prevention of coronary artery disease is probably still prudent.46
For women interested in taking herbal remedies for the management of menopausal
symptoms, it is important to provide basic medicinal information about these agents.
Much of the data are published in German and gathered from studies performed in the
1960s. Patients should become familiar with each herb chosen, including its actions and
side effects. Some herbs can cause harmful reactions such as severe diarrhea, allergic
reactions, hallucinations and liver toxicity.
Many options are available for managing the symptoms and long-term risks associated
with menopause. Ultimately, the available treatment choices may allow
individualization of a therapeutic plan to manage menopause.
TONI M. CUTSON, M.D., M.H.S.,
is assistant medical director in the Extended Care and Rehabilitation Center at the
Geriatric Research, Education and Clinical Center of the Durham Veterans Affairs
Medical Center, Durham, N.C. She also has an appointment in the departments of
Community and Family Medicine, and Medicine at Duke University Medical Center,
Durham. Dr. Cutson graduated from Virginia Commonwealth University Medical
College, Richmond, and completed a family medicine residency at Chesterfield Family
Practice, also in Richmond. She then completed a geriatric medicine fellowship and
obtained a master's degree in health sciences from Duke University Medical Center.
EMILY MEULEMAN, M.S., R.N.C.,
is an ANCC-certified gerontologic nurse practitioner at the University of Michigan
Chelsea Family Practice Center, Ann Arbor. She obtained an undergraduate degree in
nursing at Nazareth College, Kalamazoo, Mich. She completed a master's degree in
community health nursing and post-master's gerontologic nurse practitioner courses at
the University of Michigan, Ann Arbor.
Address correspondence to Toni M. Cutson, M.D., M.H.S., GRECC #182,
Durham Veteran's Affairs Medical Center, Durham, NC 27705. Reprints are
not available from the authors.
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