Outline

• Introduction
• Which Androgen Replacement Therapy for Women?
• Birth Control or Ovarian Function and Steroidal Regulation
• Pharmacologic Therapies for PMS: SSRI's and BDZ's
• Newer, Successful Treatments for PMS
• Benzodiazepine Tranquilizers for PMS
• DHEA in Postmenopausal Women-Behavioral Effects
• References

I. Introduction

Steroids are the basis of the sex hormones, which are conventionally divided into three groups: the male sex hormones or androgens, the female sex hormones or estrogens, and the pregnancy hormones or progestins. The principal androgen hormone is testosterone, which is produced in the testes. Estradiol is the principal female sex hormone produced by the ovaries. The first few milligrams of estradiol to be isolated were obtained from four tons (!) of sow ovaries. Estradiol is responsible for the development of secondary female characteristics and participates in control of the menstrual cycle.

Progesterone is the most important progestin in human beings. It is synthesiszed in the ovary, testes, and adrenal glands from cholesterol and pregnenolone. Women need increasing in amounts of progesterone with pregancy as the uterus prepares for implantation of a fertilized egg. Progestins have an interesting metabolic conversion as Progesterone is involved in the production of Cortisol, Aldosterone, Estradiol, DHEA, Testosterone, Estriol and Estrone as well as Androstenedione.

Normal males secrete 1-5 mg of progesterone daily, and the level is only sligthtly higher in females during the egg releasing stage of the cycle. During the Luteal phase, progesterone amounts of 20-30 mg/day are released into the circulation to signal fertility and preparation for implantation in the stage known as the Premenstrual period. This phase of the menstrual cycle occurs from about 10 days to one weeks before menstruation. This monthly cycle occurs only if the egg does not implant into the uterus.

Menstruating women start to produce progesterone in their ovaries after the lutenizing hormone ( LH ) surge around the time of ovulation (usally 14 days after the first day of the cycle). The progesterone level rises and falls just before the bleeding begins. This premenstrual time is called the progesterone withdrawl phase. For some women this period is felt as an exteremely anxious, nervous, "tempermental mood." Some women find it to be an extremely depressing time with tears and feelings of low self-esteem.

Until recently, progesterone given in the form of vaginal or rectal suppositories was widely prescribed for PMS. This treatment was based on results of uncontrolled studies indicating that some women had a decreased level of progesterone during this time and experienced a range of unpleasant symptoms called Premenstrual Syndrome (PMS).

This time of the month ranges in symptoms from mild cramps to wild emotion al swings that somewomen report can drive a woman nuts and even to murder. PMS has been attempted as a defence for a murder in the UK. However, not all women suffer forom this condition. PMS is more common in women with irregular menstrual cycls, little exercise and creates cravings for salt and/or sugar. More recently, natural progesterone has been shown to be more effective than placebo or synthetic forms in treating PMS symptoms. Calcium supplements have also been found to abolish the moods and cravings. Moreover, there is also evidence that both the physical and emotional symptoms of PMS may be progesterone-induced in these women.

In controlled studies, the administration of synthetic progesterone to normal women commonly resulted in increased breast tenderness, bloating of the abdomen and extremities, and emotional lability. These symptoms of excess are almost identical to the symptoms of deficiency of Progesterone. Therefore, the use of synthetic progesterone, Provera or medroxyprogesterone in the treatment of PMS cannot be advocated in the treatment of PMS. Natural Progesterone sold OTC in health stores as Progest® or by prescription as found in the WellnessMD product EstroCreme® . Natural progesterone in small doses of 25-100 mg per day boosts the low levels which might induce swelling.

In a 25 year study on women in England reported in the Lancet in 1983, it was reported that at least 13 days of progesterone were needed each month to provide protection against breast cancer. Even women who took only 10 days of progesterone, from the 16-25 day of each cycle ran a slightly higher risk of breast cancer and had less protection than the women who took progesterone for a full 13 days.

Progesterone competes with Aldosterone, the salt regulating hormone. Progesterone can prevent salt from being absorbed leading to fluid retention. Progesterone raises the temperature in man and and has hypnotic effects on the brain. Progesterone also acts on the respiratory system to decrease carbon dioxide levels in the blood and in the lungs. One can see how a deficiency of progesterone might aggravate the PMS symptoms. Many women benefit from small amounts of extra progesterone during the premenstrual time of the month. Raising progesterone slightly also prevent cravings for sweets which occur with huge swings of progesterone. Progesterone even affects levels of amino acids and lipid metabolism. Increasing calcium to 1500mg a day for one week premestrually, helps to stimulate progesterone production and decreases PMS symptoms considerably.

II. Which Androgen Replacement Therapy for Women?

Although the postmenopausal ovary remains an important source of testosterone (T) production, there is nevertheless a decline in total circulating androgen levels with age. A role for androgen replacement in addition to estrogens in some postmenopausal, particularly ovariectomized, women is increasingly gaining acceptance.

Two existing testosterone preparations, oral testosterone undecanoate (TU) and subcutaneous testosterone implants, with a new matrix transdermal delivery system for T were compared in a UK study. T Levels rose regardless of mode of intake, oral, transdermal or implants. TU produced inappropriate high T levels at all doses, with wide variations between subjects, confirming that TU is unpredictably absorbed and unlikely to be satisfactory for use in women. Subcutaneous testosterone implants produce unphysiological T levels for at least 1-2 months.

The transdermal organogel delivery system in TestoJel® used twice weekly , maintained relatively stable T levels within narrow ranges. The conclusion that reached was that transdermal systems may be of value for androgen therapy in postmenopausal women because they provide a highly controllable way of delivering T noninvasively and reliably, and achieve mean physiological levels not possible with existing methods.

III. Birth Control or Ovarian Function and Steroidal Regulation

Steroids are also the active ingredients of birth control pills, and they work by "tricking" the body into "believing" that it is pregnant, i.e. they chemically mimic pregnancy. One typical birth control pill contains 2.5 mg of norethynodrel as a main active ingredient. RU-486 has received a great deal of publicity as "the morning after pill", and it has been used in France since 1988. Its introduction into this country has been the source of controversy.

Steroid hormones regulate neuronal function, including behavior. Using rats as our model system, studies focusing on actions of the ovarian steroids, estradiol and progesterone, in brain regions (e.g., hypothalamus, preoptic area) that regulate female reproductive physiology. Estradiol and progesterone modify the way hypothalamic neurons respond to released neurotransmitter in humans as well during the PMS.

IV. Pharmacologic Therapies for PMS: SSRI's and BDZ's

Dr. Mortola, Director of Reproductive Endocrinology at Cook County Hospital in Chicago, Ill. notes:

"At present, the most likely hypothesis of PMS pathogenesis is that ovarian steroids, acting through alterations in central neurotransmitters, are responsible for symptoms of PMS. In particular, serotonin (5-HT) and gamma-aminobutyric acid (GABA)-mediated mechanisms appear important in the syndrome. In the rat, serial injection of progesterone (P4) results in increased serotonin (5-HT) uptake in several areas of the brain as well as increased 5-HT turnover. During the normal estrous cycle, 5-HT receptors in the median forebrain undergo cyclic fluctuations, being upregulated following ovulation."

During the normal premenstrual phase in humans, decreased 5-HT uptake by platelets has been reported following ovarian steroid withdrawal. This fluctuation in 5-HT uptake has been correlated with the severity of some PMS symptoms. Differences in platelet 5-HT uptake mechanisms have also been noted in women with PMS. Similar alterations have been demonstrated in whole-blood 5-HT. In addition, the 5-HT metabolite, 5-HIAA, has been measured in urine throughout the menstrual cycle, with levels peaking at midluteal phase and declining in the late luteal phase. The new SSRI's Prozac® , Paxil®, Zoloft®, Serzone® , Wellbutrin® , and Effexor® have been found effective in PMS, anxiety and depression. These agents act by increasing 5-HT levels and downregulating receptor sensitivity.

V. Newer, Successful Treatments for PMS

Fluoxetine vs imipramine. In humans, the 5-HT reuptake inhibitor, fluoxetine, has been demonstrated to be effective in the treatment of PMS in independent double-blind, placebo-controlled studies.[12,14,15] This proven efficacy as well as its safety profile make this agent effective therapy for women who meet the full criteria for PMS. Mortola and Moossazadeh[16] compared the effects of fluoxetine with those of the tricyclic antidepressant imipramine; the investigators demonstrated that the efficacy of fluoxetine in PMS is not due to the agent's generalized antidepressant effects. When 30 women treated with fluoxetine were compared with 20 women treated with imipramine, a significant response was noted in 21 of 30 (70%) subjects treated with fluoxetine versus 5 of 20 (25%) treated with imipramine (P<.005). A uniformly high response to fluoxetine was noted in women presenting with either anxious or depressed symptoms of PMS and those presenting with a premenstrual appetite or sleep disturbance.

Although the majority of studies have utilized a regimen of daily administration of SSRIs throughout the menstrual cycle, there is evidence that limiting administration of fluoxetine to the luteal phase of the cycle is effective in treating PMS patients. When prescribed in this way, a 20-mg daily dose is given after the presumed time of ovulation (day 16 of the usual 28-day cycle) until the second day of the next cycle. Because the duration of side effects is shorter when fluoxetine is limited to the luteal phase of the cycle, this is the optimal starting regimen for PMS patients. However, although this treatment may be effective using fluoxetine, pharmacokinetic differences between fluoxetine and other SSRIs are too great to permit these results to be generalized to other drugs in this class.

VI. Benzodiazepine Tranquilizers for PMS

The efficacy of alprazolam in the treatment of PMS at a dose range is 0.25mg 4 times a day during the luteal phase of the cycle. Occasionally, higher doses of 0.5mg up to 4 times a day are required. Although efficacy with this regimen has been demonstrated, clinically, many patients report significant improvement when the medication is taken as needed during the luteal phase.

Adverse effects of alprazolam. The side effect of greatest concern with alprazolam is its potential for addiction. For this reason, the use of this agent in the treatment of PMS should be carefully restricted to luteal phase administration in the reliable patient. Addiction to alprazolam has not been reported when restricted to use during this prescribed time interval.Administration of alprazolam has not been demonstrated to be safe in pregnancy and has been reported to cause lethargy in the infants of nursing mothers. Therefore, women taking this agent for PMS should be instructed to use reliable methods of birth control. Because of the variable effects of oral contraceptives on PMS symptoms, barrier methods are preferred.

According to Dr. Mortola, patients who present with PMS should be carefully evaluated to establish correct diagnosis. Those who meet all criteria for PMS, with the exception of an identifiable disruption in lifestyle, should be considered to have a subclinical form of the disorder. These women should first be prescribed an exercise regimen and be permitted to experiment with dietary modification. Although some dietary modifications, such as the addition of Calcium, Evening Primrose Oil, Vitamin B6, and Magnesium have shown positive results in clinical trials, some women who meet the criteria for PMS, including lifestyle disruption, may respond adequately to treatment with exercise alone, the majority require pharmacologic intervention for adequate symptom management.

The first-line therapy for such patients should be fluoxetine given from day 16 of the menstrual cycle until the second day of menstrual flow. In cases where this treatment is ineffective or accompanied by undesirable side effects, treatment with either an SSRI given in a continuous daily fashion or alprazolam given on an as-needed basis is recommended. Patients who are unresponsive to these treatments are best treated with a GnRH agonist plus estrogen/progestin "add-back." Other agents, such as danazol and spironolactone, should be reserved for women with more specific symptoms, particularly headache and water retention. The use of synthetic progesterones or oral contraceptives has not been demonstrated to be effective in treating for PMS.

VII. DHEA in Postmenopausal Women-Behavioral Effects

Aging in women and men is characterized by a progressive decline of circulating dehydroepiandrosterone (DHEA) levels and its sulfate ester (DHEAS). The improvement of well-being described in postmenopausal women treated with DHEA suggests that this steroid may exert specific actions on the central nervous system (CNS). The postmenopausal period is associated with several neuroendocrine modifications. The decrease of circulating levels of beta-endorphin is considered a hormonal marker of those changes. DHEAS (50 mg/day), orally with and without transdermal estradiol (50mg patch) mean basal serum DHEA, DHEAS, androstenedione, and testosterone levels significantly increased after treatment, while no changes were shown in the group receiving estradiol alone. Our EstroCreme® product contains both DHEA and estrogen and progesterone along with T for women.

Serum estradiol, estrone, GH and plasma beta-endorphin levels significantly increased progressively for the three months of treatment, with higher levels for estrone and estradiol in subjects receiving estradiol alone or plus DHEAS. In all women tested, the treatments were associated with similar and progressive improvement. After each of the treatments, the beta-endorphin response was completely restored and was similar, independent of the kind of therapy. Restoration of the beta-endorphin response to specific stimuli suggests that DHEAS and/or its active metabolites modulates the neuroendocrine control of pituitary beta-endorphin secretion, which may support the therapeutic efficacy of the DHEAS on behavioral symptoms.

The latest research in balancing estrogen/progestin action, the consequences of estrogen/testosterone loss, and the comprehensive benefits of menopausal hormone replacement with all hormones are discussed in the Practical Guide To Wellnesss 2000 series.

For more information on hormones, please go to our sister website, www.hormonenews.com .

VIII. References

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