Female Sexual Hormones Indications and Therapy In puberty, a woman has about 400,000 ovules, at the age of 40-44 years about 17,000 only. On average, each grown-up woman (still having ovulation) loses a potential female hormones producing ovule every hour, i.e. per menstruation about 600 ovules get lost. Already with the age of 30-35 years, a slight Progesterone deficiency often occurs, with the age of 40-45 years a slight Estrogene deficiency follows most of the time. This hormone deficiency is usually only treated at the beginning of the menopause (+/- 50 years). However, it would be important to treat already the first signs of hormone deficiency in order to prevent irreversible consequences, which means to start an adequate HRT (Hormone Replacement Therapy) considerably earlier. During menstruation, the Estrogene level is at first reduced in the follicular phase while it is often too high in the luteal phase. This can lead to a Progesterone deficiency in the second half of the. In the menopause the Estrogene level is reduced by approximately 83%, the DHEA level by approximately 74%. Woman s Androgens deficiency is amplified at the age of about 65 years. In the post-menopause Estrone becomes the main Estrogene while, before menopause, the essentially more active Estradiole is the main Estrogene. Formation of sexual hormones within 24 hours (average values) follicular phase beginning follicular phase end luteal phase menopause Estradiole 40 µg 400 µg 250 µg 15 µg Estrone 75 µg 350 µg 250 µg 40 µg Testosterone 180 µg 240 µg 160 µg 120 µg Dihydrotestosterone 300 µg 70 µg 60 µg 40 µg Androstandiole 35 µg 40 µg 35 µg 30 µg Androstendione 2,6 mg 4,7 mg 3,4 mg 1,4 mg DHEA 7,0 mg 7,0 mg 7,0 mg 3,0 mg DHEA-S 12,0 mg 12,0 mg 12,0 mg 5,0 mg Progesterone 1,0 mg 2,0 mg 25 mg 0,5 mg 17-Hydroxyprogesterone 0,5 mg 4,0 mg 2,5 mg 0,5 mg (Vermeulen A, p.98 in Medecine de la reproduction, Mauvais et Jarvis P et al, 3 ed. 1997, Ed Flammarion - Paris)
Blood test for a screening on deficiency of female hormones reference value (17-50 years) average value = optimal? LH (> P) 0,2-12mIU/ml 6,1mIU/ml FSH (> E2) 2-13mIU/ml 7,5mIU/ml Estradiole = E2 follicular phase (7 th day) at ovulation (13 th -14 th day) luteal phase (21 st day) Estrone = E1 follicular phase (7 th day) at ovulation (13 th -14 th day) luteal phase (21 st day) Estriole = E3 Slight decrease at ovulation (pregnancy: 0-31,0ng/ml) 30-150pg/ml 150-600pg/ml 100-210pg/ml 30-150pg/ml 60-600pg/ml 40-200pg/ml 40-100pmol/l 90pg/ml 375pg/ml 155pg/ml 90pg/ml 330pg/ml 120pg/ml 70pmol/l Progesterone follicular phase (7 th day) at ovulation (13 th -14 th day) luteal phase (21 st day) 0,3-1,0ng/ml 0,5-1,5ng/ml 3-27ng/ml 0,65ng/ml 1,0ng/ml 15ng/ml Transcortine (CBG) 20-50mg/l 35mg/l Testosterone (at ovulation) free Testosterone Dihydrotestosterone Androstendione (at ovulation) SHGB 150-600pg/ml 1,5-1,9pg/ml 100-450pg/ml 1,0-3,5pg/ml 41-79nmol/l 275pg/ml (f), 400pg/ml (l) 1,7pg/ml 200pg/ml (f), 300pg/ml (l) 1,75pg/ml (f,l) 60pmol/l The hormone levels in blood are ideally determined on day 7, 13 or 14 and 21 in case of a 28- day-. If a hormone cream is used, it should not be applied for 2 days in the area where blood sample is taken as the result is falsified otherwise. It is necessary to test on 3 different days of the as, for example, women in the perimenopause can have an Estradiole deficiency during the follicle phase, even if they have an adequate Estradiole level during the luteal phase of the. In order to determine the correct dosage, not only the measured hormone levels should be taken into consideration but also the patient s hormone deficiency symptoms.
1. Estradiole (micronized) Therapy: Resorption of Estradiole in case of different application forms: a) Topical: Estradiole is very well absorbed in form of an alcoholic liposomal gel. This application leads to a physiological ratio between Estradiole and Estrone. The sexual hormone binding globulins do not increase when given a dosage of up to 3mg Estradiole. b) Sublingual: Estradiole is absorbed very quickly but also eliminated very quickly. An excessive metabolisation of Estradiole into Estrone results. c) Oral, suspended in oil: Estradiole is increasingly metabolised into Estrone. The sexual hormone binding globulins (SHBG) are increased. These are binding Androgens mainly. As only the free, not protein bounded from is active the oral application may possibly cause an Androgen deficiency. HDL increases more by orally applied Estrogens than by transdermal application. d) Vaginal: Estradiole is vaginally very well absorbed; the ratio of Estrone to Estradiole is physiological. After approximately 4 hours, the maximum blood level is reached, after 24 hours high values are still measured. However the effect of Estradiole on the endometrium using this application form is not yet studied sufficiently. Application of liposomal gel: The gel is applied in the inner sides of the upper arms and on the shoulders. The gel should be massaged into the skin by using at least 10x rotary movements on the skin surface: thereby a widely spread application and a better blood circulation of the skin is achieved, resulting a better penetration and absorption. Body creams and lotions should not be put on the application area as well as oil baths should not be taken before, otherwise the skin has to be cleaned with soap before the application of gel. In summer sun cream should be applied on the outer sides of the arms and the inner sides of the arms should be left free for the Estradiole gel. (Alternative: in summer change to Estradiole plasters, but not optimal.) Average daily dosage: orally / encapsulated in oil 0.6mg-2,25mgEstradiole in the morning liposomal gel 0,06% 1,0g-4,0g liposomal gel = 0,6mg-2,4mg Estradiole The liposoaml gel is filled in a special airless system which gives 1g liposomal gel The dosage has to be adjusted individually on the basis of the evaluation of the deficiency symptoms. The patient should control these symptoms once a week and increase the dosage, if necessary still during the in steps of 0,75mg Estradiole each. It is also possible to start the accordingly higher dosage at the beginning of the next. From a dosage of more than 2mg Estradiole per day, it is recommended to split the daily dosage (2/3 of daily dosage in the morning, 1/3 of daily dosage in the evening). Otherwise a decrease of blood levels can occur which may result in a bleeding.
Estradiole transdermal as plaster: Disadvantage: For the treatment of osteoporosis TTS 50 is not sufficient, giving TTS 100, too much Estradiole is released at the first day. [TTS = Transdermal Therapeutic System] The oral application of Estradiole may possibly lead to an Androgen deficiency than the topical application (according to Hertoghe). 2. Progesterone (micronized) Average daily dosage: orally / encapsulated in oil: 100-200mg (preferably in the evening, Progesterone makes tired) topical / cream or liposomal base: 10-80mg (e.g. 3%: 1g = 30mg) (preferably in the evening, Progesterone makes tired) vaginal suppositories: 50mg, 100mg, 200mg,400mg/day Exception: pregnancy Very high dosages, up to 600mg per day, may possibly be necessary during pregnancy. The dosage has to be split in this case. Vaginal suppositories: To pregnant women running the risk of miscarriage, a small part of the daily Progesterone dosage should be administered vaginally and the major part orally. The diuretic effect of the hormone of the corpus luteum (Progesteron) as well as the effect of lifting spirits is the highest if vaginal application is used. Therapy with Estradiole and Progesterone Therapy with Estradiole and Progesterone for women in the postmenopause: Progesterone and Estradiole are given from 1 st -25 th day of the month, after this a break of 5-6 days is following. If deficiency symptoms occur during these hormone free days, the break can be reduced. A short break is always recommended, possible generated cancer cells do not receive any stimulation during this therapy free period and then perish by oneself. Even if a woman does not wish to have a bleeding anymore, it seems to be reasonable to initiate a bleeding all 3-4 months (Hertoghe). Therapy with Estradiole and Progesterone for women still having a : Hormones suspended and encapsulated in oil: Estradiole is given from 1 st -25 th day of menstrual. Progesterone is given from 13 th -25 th day of menstrual ; in some cases a prior administration may be necessary (from the 8 th day of menstrual ).
Therapy of premenstrual syndrome (PMS): Only with Progesterone: from 18 th -25 th day of the menstrual 100-200mg orally encapsulated in oil in the evening. Treatment of an ovarian insufficiency: Pre-Menopause Post-Menopause only Progesterone Estrogene 5 th -25 th day of the 1 st -25 th day of the Progesterone 18 th -26 th day of the 15 th -25 th day of the 13 th -25 th day of the without 1 st -25 th day of the Androgens without interruption without interruption Complaints: In the case of intermediate bleeding, an Estrogene deficiency often exists increase Estrogene dosage Droopy breasts Estrogene deficiency Breast pain Progesterone deficiency a) pain in the first half of the often too much Estrogene b) pain in the second half of the often lack of Progesterone (then from 10 th -14 th day 50mg Progesterone encapsulated in oil and from 15 th -25 th day 100-200mg Progesterone encapsulated in oil) Intermediate bleedings Intermediate bleedings are often a sign of Estradiole deficiency. In a normal, the hormone Estrogene is considerably reduced shortly after ovulation. Such a reducing of hormone levels can release a short bleeding. By a poor intermediate bleeding, the Estradiole dosage has to be increased and the therapy is continued. If a normal menstrual bleeding occurs, this is to be considered as the first day of the new. After a break of 5 days, the therapy is restarted again with a higher Estradiole dosage. If intermediate bleedings still occur despite higher Estradiole dosages, Progesterone should be given from the 18 th day on. Intermediate bleedings may also be a sign of a Progesterone deficiency.
Breast pain Breast pain in the first half of the : This indicates an overdosing of Estradiole. Estradiole overdosing symptoms have always been occurred only in the first half of the. Estradiole deficiency symptoms may in contrast occur during the whole. Breast pain in the second half of : This is usually always a matter of a Progesterone deficiency. If having breast pain in the second half of the, the Progesterone dosage has to be increased immediately in order to avoid an aggravation. For the next, the dosage has to be adjusted. Possibly Progesterone must be given already on the 10 th day: 10 th -14 th day 50mg Progesterone encapsulated in oil 15 th -25 th day 100-200mg Progesterone encapsulated in oil For women who still have the uterus, Estradiole should always be combined with Progesterone. When determining the Estrogene and Progesterone levels, the Androgen level should also be measured because the dosage of Estradiole may cause an Androgen deficiency. However, Androgen should be given only, if the levels are too low and/or symptoms of an Androgen deficiency occur respectively. Therapy of hormone deficiency in the peri-menopause: A combination of Progesterone, Estradiole and / or an Androgen is required. The balance between the individual hormones is very important. A Progesterone deficiency may for example also result due to an Estrogene surplus. When administrating Estrogene and Progesterone, Androgens should always be taken into consideration as well as the other way around. Dosage-comparison of Progesterone orally micronized and usual Gestagen compounds: 300mg micronized Progesterone 10mg Medroxyprogesteroneacetate (Clinofem) 0,7-1mg Norethisteron (or Acetate) (Primolut Nor) 150µg DL-Norgestrel Whitehead M. et al, Obstet Gynecol, 1990, 75-595-765 100mg Progesterone = 10mg Dydrogesterone (Duphaston) Androgen deficiency with or without Progesterone/Estradiole deficiency 1. the best is DHEA orally 5-25mg encapsulated in oil in the morning 2. occasionally Testosterone a) transdermal as liposomal gel or vanishing cream: 7-15mg per day (1%: 1g = 10mg) b) Testosteroneundecanoat (Andriol): 1x40mg all 2-3 days (especially for constant low libido) c) Mesterolon (Proviron): ½ to 1 tablet containing 25mg per day
Aim: optimal serum DHEA level approximately 250µg/dl urine DHEA level approximately 0,35-0,4mg per 24h after a few months: more muscle strength, more self-confidence, more muscles Age-related diseases Cardiovascular diseases Are the number 1 causes of death for women. The risk is already increased in the perimenopause. The cardiovascular risk is about half reduced for women who have taken Estrogens for a few years (also birth-control pills) than for women who have never taken Estrogens. Estrogens increase the HDL (these are more increased by orally administered Estrogens than by transdermal Estrogene) and reduce the LDL. Furthermore, they reduce blood pressure and body weight. Ageing women gain less weight with Estrogens than without them. Transdermal Estradiole is reducing more the fat mass than oral Estradiole. Osteoporosis The bone loss has already started at the age of 30 years. If young women have surgically removed their ovaries, the bones loose their density. Studies prove that Estrogens increase the bone density and do not only prevent the bone loss. The bone density is more increased by transdermal application than by oral application. Men suffer from osteoporosis more rarely because they have more Estrogene precursor. 90% of Estradiole is generated in the ovaries of woman before the menopause, after the menopause 90% of Estradiole is generated by the transformation of other hormones. The minimal plasma level in order to avoid bone loss is 60-90pg/ml Estradiole. Rheumatoid arthritis Can be avoided by Estrogens. Women who have taken birth-control pills have half risk compared to women who have never taken Estrogens. Fibromyalgie Muscle pain is improved by the application of female sexual hormones. Dementia Is improved by application of Estrogens, the same may possibly apply to Alzheimer s disease. A study has shown that the risk of Alzheimer s disease is 8 times lower for 74 years old women that have taken Estrogens for 13,6 years on average compared to women who have never taken Estrogens. Growth hormone level The growth hormone level decreases in case of Estrogene deficiency. Estrogene administered orally is increasing the growth hormone level but decreases IGF1, Estrogene applied transdermally is not leading to a decrease of IGF1. Breast cancer There is often a Progesterone deficiency with breast cancer. The risk of breast cancer is 6 times higher for women having a Progesterone deficiency than for women without Progesterone deficiency.
Contraindications for a therapy with Estradiole Thrombosis A heavy thrombosis is a contraindication. For a slight form, Estradiole transdermal can be used (not orally!), but in low dosages. Gallbladder diseases Are not considered as a contraindication. Endometriosis, oedemas, fibrocystic breast diseases It should be given more Progesterone and less Estradiole.