Hormones and the Menstrual Cycle
The ovary and the adrenals are the source of two types of “female” hormones, estrogens and progesterone. At least six different estrogens have been identified, but only estrone, estradiol (E ), and estriol are circulate in significant quantities in the blood. Estrogen levels begin to increase during the first part of the menstrual cycle, (follicular phase) peak just before ovulation, and then decline slowly until they reach their lowest point at the onset of menses. The principal function of the estrogens is to cause cellular proliferation and growth of the tissues of the sexual organs and tissues related to reproduction.
Progesterone is a hormone that prepares the lining of the uterus for the fertilized egg and maintains pregnancy. The name tells the story, promotes gestation hormone. Progesterone is derived primarily from the corpus luteum in the ovary after ovulation. When the follicle ruptures, it is transformed into the corpus luteum. Progesterone is also produced by the placenta during pregnancy and in small amounts by the adrenal cortex. Progesterone is a “precursor” hormone that is converted into other steroid hormones like testosterone, estrogens, cortisol and aldosterone.
During the follicular phase (before ovulation), the concentration of progesterone in the bloodstream is less than 1 ng/ml, although still present in much higher amounts than estrogen. Ovulation initiates the second half (luteal phase) of the cycle, and at this time progesterone levels in the blood increase up to 20 ng/ml and may be 140 times as high as estrogen. As its levels increase, progesterone acts as a powerful antagonist to the action of estrogens. A sharp decline in progesterone initiates the onset of the menses.
Pre-menstrual syndrome (PMS) affects millions of women to varying degrees. It has been estimated that 7090% of all women regularly experience at least one symptom of PMS and in 10-20% of women symptoms are severe enough to be incapacitating. Once dismissed as female neurosis or physical frailty, PMS is now a recognized medical entity that clinically characterized as the cyclical occurrence or exacerbation of one or more physical or psychological symptoms during the luteal phase (after ovulation) of the menses. Symptoms, which include irritability, emotional lability, bloating, breast tenderness, hypoglycemic symptoms, food cravings, weight gain and depression, improve or generally disappear entirely with the onset of the menses.
While numerous hypotheses have been advanced to explain the etiology of the syndrome, most have centered on the ovarian hormones, estrogen and progesterone and the balance between them. No one explanation suffices to explain all types of PMS, but it is generally held that many cases are caused by elevated levels of estrogen, resulting from excessive endogenous production or from a failure of the liver to adequately metabolize estrogens to their excretable forms. A concomitant theory (since progesterone is biologically an antagonist to estrogen) posits low progesterone, or progesterone lowin relation to estrogen as the cause of PMS. An excess of prolactin, elevated free luteinizing hormone levels, and deficiency of brain amines (serotonin and dopamine) are also considered to be involved either independently 3 or as a consequence of the estrogen-progesterone ratio.
Initial efforts to manage PMS by administering progesterone were complicated by unsatisfactory ways of delivering the hormone. Because of the importance of protecting the human organism from the effects of hormones from other species that may be consumed in the diet, a sophisticated system exists to eliminate them. Hormones that are taken orally are shunted first to the liver, where they are converted to less active forms for elimination. This first-pass by the liver makes supplementing with oral hormones difficult. In fact in a leading medical text, Harper’s Biochemistry, “progesterone is ineffective when given orally.” Twenty-five years ago a British physician, Katherina Dalton, M.D., began using progesterone to treat PMS. She obtained good clinical results using intramuscular injections, vaginal suppositories or rectal pessaries of natural progesterone. Her pioneering work prompted others to use natural progesterone in non-oral forms, which has been used successfully now by doctors all over the world for decades.
Exercise and avoiding caffeine, refined carbohydrates, and alcohol also help reduce PMS. In addition, certain types of PMS respond to magnesium, vitamin E, essential fatty acids, and/or vitamin B6. These nutrients modulate hormones and chemicals in the brain that appear to be the primary contributors to PMS. For example, vitamin B6 is a coenzyme in the final step of the formation of dopamine and serotonin. These two biochemicals play a role in mood, anxiety, depression, stamina, sleep, etc. Excessive levels of estrogens, which compete with B6, may lead to a diminished biosynthesis of serotonin from tryptophan.
Natural vs Synthetic Progesterone
It is important to distinguish between the “natural” progesterone successfully used by Dr. Dalton and synthetic progestational agents such as progestins, progestagens, or gestoizens that are present in oral contraceptives. Progesterone refers to a specific molecule, the hormone produced by the ovaries or adrenal glands. All progestins are synthetic hormones that closely resemble progesterone, but differ in important ways. The natural and synthetic hormones share the ability to sustain human secretary endometrium but progestins do not have the full range of biological activity of progesterone. Progestins are associated with a wide range of undesirable side effects that often undermine patient compliance. Significantly, progestins’ appear to inhibit biosynthesis of progesterone, lowering serum levels of the hormone and aggravating conditions linked to inadequate progesterone.  Synthetic progestins lower the “good” HDL cholesterol and reverse the benefit of estrogen on heart disease.
In Lorraine A. Fitzpatrick, M.D.’s August 1999 Mayo Clinic study of 176 women taking natural oral progesterone after they had taken synthetic progestins, 34% felt more satisfied with the natural progesterone compared to the prior progestins. The women reported 50% improvement in hot flashes, 42% improvement in depression, and 47% improvement in anxiety. The natural oral “progesterone also controlled breakthrough bleeding better than the synthetic hormone.”
Several species of the yam family (dioscoreaceae, also called barbasco in Central America) as well as soybeans, contain significant amounts of diosgenin, a complex molecule which converts readily and inexpensively to pregnenolone and then into a “natural” progesterone which is essentially identical to the hormone produced in a woman’s body. Both progestins and the “natural” progesterone derive from diosgenin, but because a natural hormone cannot be patented by a pharmaceutical company, an alteration of the molecule was required in order to secure patent rights … hence progestins.
Female athletes who exercise to the point of having anovulatory cycles with subsequent loss of progesterone experienced bone loss despite normal levels of estrogen levels. 
Given the first-pass liver loss with oral progesterone preparations and the inconvenience of injections and suppositories, a different route of administration of the natural progesterone is highly desirable. The development of transdermal creams containing progesterone combined with plant extracts containing diosgenin have proved to be a very effective alternative. Since transdermal absorption bypasses the liver, smaller amounts of progesterone are required to accomplish results. Over the past 10 years enough clinical evidence has accumulated to verify that topical natural progesterone is an effective tool for the management of a majority of PMS cases. 
Progesterone and Menopause
By the time a woman reaches menopause, gonadal hormone production, which has been on a slow, steady decline since her 30’s, reaches its lowest point. With the exception of small amounts produced by the adrenal cortex, a woman’s production of both progesterone and estrogen after the menopause is negligible, and the biological consequence of this loss are dramatic.
For decades the focus of research on the climacteric and its health risks was exclusively on estrogen (specifically, synthesized estradiol) probably because it was regarded as the most potent of the female hormones. Additionally, it was known to mediate the activity of osteoclasts (bone resorption cells), an important consideration in light of the risk of serious health consequences of osteoporosis. Despite a growing list of concerns surrounding the use of supplemental estrogen (including increased risk to cancers of the breast, cervix, and endometrium) it has for years been the standard of care for menopausal complaints and the prevention of osteoporosis.
Progesterone and Osteoporosis
While conventional estrogen replacement therapy (ERT) does retard bone resorption and decreases the incidence of fracture for a number of years it does not stop or reverse the progressive dismantling of bone.  As concerns regarding the side effects of ERT continued to mount estrogen began to be paired with progestins to balance the tissue stimulating effects of estrogen and confer protection against estrogen-related cancers. Analysis of several studies on the effect of combined progestin-estrogen therapy indicates that progestins do appear to improve bone density, but their use is accompanied by a long list of unacceptable potential side effects.
Since these observations, the role of natural progesterone in osteoporosis has been investigated, most notably John Lee, M.D., a California clinician and researcher. In a recent article, Dr. Lee reviewed several important observations concerning the role of progesterone in bone formation:’
The correlation of osteoporosis with hormone decline is stronger for progesterone than for estrogen. Bone loss begins well before the actual onset of menopause, a time when estrogen is still sufficient but when progesterone levels have already begun to decline.
There is evidence of progesterone receptors in osteoblasts (bone building cells) but not for estrogen, indicating a bone-building role for progesterone. 
In the early 80’s Dr. Lee began using transdermal progesterone (derived from wild yams) to treat his female osteoporotic patients. Initially, it was prescribed in conjunction with estrogen, but later used alone (except in cases of vaginal dryness), with a program of vitamins, modest calcium supplementation, and dietary advise. Bone mineral density (BMD) was monitored by lumbar dual photo absorptiometry, and other factors such as hypothyroidism and achlorhydria were adjusted as required. Dr. Lee observed BMD increases of 10-15% within 6 months and 20-25% in 3 years.Mean 3-year increase in BMD was approximately 15% with even greater increases in those with the lowest initial BMD. Therapy produced relief of bone pain, increased physical activity, height stabilization, and fracture prevention. The benefits of progesterone were independent of age, time from menopause, or estrogen use.”
Other significant benefits were observed in Dr. Lee’s patients: Women with endometrial hyperplasia when using estrogen alone reverted to normal endometrium on progesterone. Women who experienced fibrocystic breast disease while on estrogen alone reported improvement. Similarly, women who developed hypertension while on estrogen became normotensive when switched to progesterone. Lipid profiles improved, and a general feeling of well being without unpleasant side effects was characteristic of his patients.
Other menopausal symptoms, including hot flashes, night sweats, declining libido, and emotional irritability/ lability also respond well to progesterone therapy. Some patients reported an improvement in skin quality and a decrease in “brown” spots.
1. Basic and Clinical Endocrinology, Lange Medical Publications, lst Edition, 1983:p.376.
2. Gaby, Alan. The Doctor’s Guide to Vitamin B6, Rodale, 1984, p. 25.
3. London, R. et al. Evaluation and Treatment of Breast Symptoms in Patients with PMS. Journal of Reproductive Medicine, 1983;28: 503-508.
4. Chakmakjian, Z. A Critical Assessment of Therapy for the Pre-menstrual Tension Syndrome. J. of Reproductive Medicine 1983;28: 532-537.
5. Whittaker, N. PMS and Post-partum Depression, Mothering 1983: 27-34.
6. Kamen, Betty. Hormone Replacement Therapy, Yes or No, Nutrition Encounter, Inc. 1993: 210.
7. Lee, John. Successful Menopausal Osteoporosis Treatment Restoring Osteoclast/Osteoblast Equilibrium. Townsend Letter for Doctors, 1994; 133-134
8. Ibid. 900-905.
9. Prior, J, Vigna Y. Spinal bone loss and ovulatory disturbances New England JMedicine 1990; 323:1221-7
10. Prior, J. Progesterone as a bone-trophic hormone, Endocrine Reviews 1990; 11: 386-398.
11. Lee, John. Osteoporosis Reversal, The Role of Progesterone, International Clinical Nutrition Review, 1990; 10:384-391.