Estradiol
From DrugPedia: A Wikipedia for Drug discovery
Estradiol (17β-estradiol) (also oestradiol) is a sex hormone. Mislabelled the "female" hormone, it is also present in males; it represents the major estrogen in humans. Estradiol has not only a critical impact on reproductive and sexual functioning, but also affects other organs including bone structure.
Generally refers to the 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. In humans, it is produced primarily by the cyclic ovaries and the PLACENTA. It is also produced by the adipose tissue of men and postmenopausal women. The 17-alpha-isomer of estradiol binds weakly to estrogen receptors (RECEPTORS, ESTROGEN) and exhibits little estrogenic activity in estrogen-responsive tissues. Various isomers can be synthesized.
Contents |
Production
During the reproductive years, most estradiol in women is produced by the granulosa cells of the ovary|ovaries by the aromatization of androstenedione (produced in the theca folliculi cells} to estrone, followed by conversion of estrone to estradiol by 17β-hydroxysteroid reductase. Smaller amounts of estradiol are also produced by the adrenal cortex, and in me), by the testes. Estradiol is not only produced in the gonads: in both sexes, precursor hormones, specifically testosterone, are converted by aromatization to estradiol. In particular, fat cells are active to convert precursors to estradiol, and will continue to do so even after menopause. Estradiol is also produced in the brain and in arterial walls.
Mechanism of action
Estradiol enters cells freely and interacts with a cytoplasmic target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell.
Estradiol binds well to both estrogen receptors, ERα and ERβ, in contrast to certain other estrogens, notably medications that preferentially act on one of these receptors. These medications are called selective estrogen receptor modulators, or SERMs.
Half Life: 36 hours Drug Type: Small Molecule; Approved; Investigational
Pharmacology: Estradiol, the principal intracellular human estrogen, is substantially more active than its metabolites, estrone and estriol, at the cellular level. Indication: For the treatment of urogenital symptoms associated with post-menopausal atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria).
Estradiol is the most potent naturally-occurring estrogen.
Recently there has been speculation about a membrane estrogen receptor, ERX.
Metabolism
In plasma, estradiol is largely bound to sex hormone binding globulin, also to albumin, -only a fraction is free and biologically active. Deactivation includes conversion to less active estrogens such as estrone and estriol. Estriol is the major urinary metabolite. Estradiol is conjugated in the liver by sulfate and glucuronide formation and as such excreted via the kidneys. Some of the watersoluble conjugates are excreted via the bile duct, and partly reabsorbed after hydrolysis from the intestinal tract. This enterohepatic circulation contributes to maintaining estradiol levels.
Measurement
Serum estradiol measurement in women reflects primarily the activity of the ovaries. As such they are useful in the detection of baseline estrogen in women with amenorrhea or menstrual dysfunction and to detect the state of hypoestrogenicity and menopause. Furthermore, estrogen monitoring during fertility therapy assesses follicular growth and is useful in monitoring the treatment. Estrogen-producing tumors will demonstrate persistent high levels of estradiol and other estrogens. In precocious puberty estradiol levels are inappropriately increased.
In the normal menstrual cycle estradiol levels measure typically <50 ng/ml at menstruation, rise with follicular development, drop briefly at ovulation, and rise again during the luteal phase for a second peak. At the end of the luteal phase estradiol levels drop to their menstrual levels unless there is a pregnancy.
During pregnancy estrogen levels including estradiol rise steadily towards term. The source of these estrogens is the placenta that aromatizes prohormones produced in the fetal adrenal gland.
Effects
Female reproduction
In the female, estradiol acts as a growth hormone for tissue of the reproductive organs, supporting the lining of the vagina, the cervical glands, the endometrium and the lining of the fallopian tubes. It enhances growth of the myometrium. Estradiol appears necessary to maintain oocytes in the ovary. During the menstrual cycle, estradiol that is produced by the growing follicle triggers, via a positive feedback system, the hypothalamic-pituitary events that lead to the luteinizing hormone surge, inducing ovulation. In the luteal phase estradiol, in conjunction with progesterone, prepares the endometrium for implantation. During pregnancy estradiol increases due to placental production. In baboons, blocking of estrogen production leads to pregnancy loss suggesting that estradiol has a role in the maintenance of pregnancy. Research is investigating the role of estrogens in the process of initiation of labor.
Sexual development
The development of secondary sex characteristics in women is driven by estrogens, specifically estradiol. These changes are initiated at the time of puberty, most enhanced during the reproductive years, and become less pronounced with declining estradiol support after the menopause. Thus, estradiol enhances breast development, and is responsible for changes in the body shape affecting bones, joints, fat deposition. Fat structure and skin composition are modified by estradiol.
Male reproduction
The effect of estradiol (and estrogens) upon male reproduction is complex. Estradiol is produced in the Sertoli cells of the testes. There is evidence that estradiol is to prevent apoptosis of male germ cells. <ref>Pentikäinen V, Erkkilä K, Suomalainen L, Parvinen M, Dunkel L. Estradiol Acts as a Germ Cell Survival Factor in the Human Testis in vitro. The Journal of Clinical Endocrinology & Metabolism 2006;85:2057-67 PMID 10843196</ref>
Several studies have noted that sperm counts have been declining in many parts of the world and it has been postulated that this may be related to estrogen exposure in the environment.<ref> Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet. 1993 May 29;341(8857):1392-5. PMID 8098802 </ref> Suppression of estradiol production in a subpopulation of subfertile men may improve the semen analysis.<ref>Raman JD, Schlegel PN. Aromatase Inhibitors for Male Infertility. Journal of Urology. (2002), 167: 624-629. PMID 11792932</ref>
Males with sex chromosome genetic conditions such as Klinefelters Syndrome will have a higher level of estradiol.
Bone
There is ample evidence that estradiol has a profound effect on bone. Individuals without estradiol (or other estrogens) will become tall and eunuchoid as epiphysieal closure is delayed or may not take place. Bone structure is affected resulting in early osteopenia and osteoporosis. <ref>Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER. Effect of Testosterone and Estradiol in a Man with Aromatase Deficiency. New England Journal of Medicine Volume 337:91-95 July 10, 1997 PMID 9211678</ref> Also, women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.
Liver
Estradiol has complex effects on the liver. It can lead to cholestasis. It affects the production of multiple proteins including lipoproteins, binding proteins, and proteins responsible for blood clotting.
Brain
Estrogens can be produced in the brain from steroid precursors. As antioxidants, they have been found to have neuroprotective function.<ref>Behl C, Widmann M, Trapp T, Holsboer F. 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun. 1995 Nov 13;216(2):473-82. PMID 7488136 </ref> The positive and negative feedback loop of the menstrual cycle involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulate gonadotropins.
Estrogen is considered to play a significant role in women’s mental health. A conceptual model of how estrogen affects mood was suggested by Douma et al 2005 based on their extensive literature review relating activity of endogenous, bio-identical and synthetic estrogen with mood and well-being. They concluded that the sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained estrogen low levels correlated with significant mood lowering. Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be effective after levels of estrogen were stabilized and/or restored.<ref>Douma SL, Husband C., O’Donnell, M.E., Barwin B.N., Woodend AK. Estrogen-related Mood Disorders Reproductive Life Cycle Factors.Advances in Nursing Science(2005), 28: No. 4:147-160.</ref> <ref>Lasiuk GC,.The Effects of Estradiol on Central Serotonergic Systems and Its Relationship to Mood in Women. Biological Research for Nursing. (2007), 9: No. 2:364-375. DOI: 10.1177/1099500407605600</ref>
Blood vessels
Estrogen affects certain blood vessels. Improvement in arterial blood flow has been demonstrated in coronary arteries.<ref>Collins P, Rosano GM, Sarrel PM, Ulrich L, Adamopoulos S, Beale CM, McNeill JG, Poole-Wilson PA. 17 beta-Estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation. 1995 Jul 1;92(1):24-30 PMID 7788912 </ref>
Oncogene
Estrogen is suspected to activate certain oncogenes, as it supports certain cancers, notably breast cancer and cancer of the uterine lining. In addition there are several benign gynecologic conditions that are dependent on estrogen such as endometriosis, leiomyomata uteri, and uterine bleeding.
Pregnancy
The effect of estradiol, together with estrone and estriol, in pregnancy is less clear. They may promote uterine blood flow, myometrial growth, sitmulate breast growth and at term, promote cervical softening and expression of myometrial oxytocin receptors.
Role in sex differentiation of the brain
One of the fascinating twists to mammalian sex differentiation is that estradiol is one of the two active metabolites of testosterone in males (the other being dihydrotestosterone), and since fetuses of both sexes are exposed to similarly high levels of maternal estradiol, this source cannot have a significant impact on prenatal sex differentiation. Estradiol cannot be transferred readily from the circulation into the brain, while testosterone can, thus sex differentiation can be caused by the testosterone in the brain of most male mammals, including humans, aromatizing in significant amounts into estradiol. There is also now evidence that the programming of adult male sexual behavior in animals is largely dependent on estradiol produced in the central nervous system during prenatal life and early infancy from testosterone. <ref>Harding, Prof. Cheryl F. (June 2004). "Hormonal Modulation of Singing: Hormonal Modulation of the Songbird Brain and Singing Behavior". Ann. N.Y. Acad. Sci. 1016: 524–539. The New York Academy of Sciences. doi:. Retrieved on 2007-03-07.</cite></ref> However, it is not yet known whether this process plays a minimal or significant part in human sexual behaviors although evidence from other mammals tends to indicate that it does. <ref><cite style="font-style:normal">Simerly, Richard B. (2002-03-27). "Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain" (pdf). Annual Rev. Neurosci. 25: 507–536. doi:. PMID 12052919. Retrieved on 2007-03-07.</cite></ref>
Recently, it was discovered that volumes of sexually dimorphic brain structures in phenotypical males changed to approximate those of typical female brain structures when exposed to estradiol over a period of months. <ref name="eje-utrecht"><cite style="font-style:normal">Hulshoff, Cohen-Kettenis et al. (July 2006). "Changing your sex changes your brain: influences of testosterone and estrogen on adult human brain structure". European Journal of Endocrinology 155 (155): 107–114. doi:. Template:ISSN.</cite></ref> This would suggest that estradiol has a significant part to play in sex differentiation of the brain, both pre-natal and throughout life.
Estradiol medication
Estrogen is marketed in a number of ways to address issues of hypoestrogenism. Thus there are oral, transdermal, topical, injectable, and vaginal preparations. Furthermore, the estradiol molecule may be linked to an alkyl group at C3 position to facilitate the administration. Such modifications give rise to estradiol acetate (oral and vaginal applications) and to estradiol cyprionate (injectable).
Oral preparations are not necessarily predictably absorbed and subject to a first pass through the liver where they can be metabolized and also initiate unwanted side effects. Thus, alternative routes of administration have been developed that bypass the liver before primary target organs are hit. Transdermal and transvaginal routes are not subject to the initial liver passage.
A more profound alteration is ethinylestradiol, the most common estrogen ingredient in combined oral contraceptive pills
Therapy
Hormone replacement therapy
If severe side effects of low levels of estradiol in a woman's blood are experienced (commonly at the beginning of menopause or after oophorectomy), hormone replacement therapy may be prescribed. Often such therapy is combined with a progestin.
Estrogen therapy may be used in treatment of infertility in women when there is a need to develop sperm-friendly cervical mucus or an appropriate uterine lining.
Estrogen therapy is also used to maintain female hormone levels in male-to-female transsexuals.
Estrogen and Mood
Estrogen is considered to play a significant role in women’s mental health. A conceptual model of how estrogen affects mood was suggested by Douma et al 2005 based on their extensive literature review relating activity of endogenous, bio-identical and synthetic estrogen with mood and well-being. They concluded the sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained estrogen low levels correlated with significant mood lowering. Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be affective after levels of estrogen were stabilized and/or restored.
Blocking estrogens
Inducing a state of hypoestrogenism may be beneficial in certain situations where estrogens are contributing to unwanted effects, e.g, certain forms of breast cancer, gynecomastia, and premature closure of epiphyses. Estrogen levels can be reduced by inhibiting production using gonadotropin- releasing factor agonists (GnRH agonists) or blocking the aromatase enzyme using an aromatase inhibitor, or estrogen effects can be reduced with estrogen antagonists such as tamoxifen. Flaxseed is known to reduce estradiol.<ref>Template:Cite book</ref>
Hormonal contraception
A synthetic form of estradiol, called ethinylestradiol is a major component of hormonal contraceptive devices. Combined forms of hormonal contraception contain ethinylestradiol and a progestin, which both contribute to the inhibition of GnRH, LH, and FSH. The inhibition of these hormones accounts for the ability of these birth control methods to prevent ovulation and thus prevent pregnancy. Other types of hormonal birth control contain only progestins and no ethinylestradiol.
List of estradiol medications
The following are marketed versions of estradiol:
- Oral versions: Estrace, Activella (also contains a progestin), estradiol acetate, Progynova, estrofem
- Transdermal preparation: Alora, Climara, Vivelle, Vivelle-Dot, Menostar, Estraderm TTS
- Ointments: Estrasorb Topical, Estrogel, Elestrin
- Injection: Estradiol cypionate: Lunelle monthly injection, Estradiol valerate
- Vaginal ointment: Estrace Vaginal Cream, Premarin Cream
- Vaginal ring: Estring (estradiol acetate), Femring
Estradiol is also part of conjugated estrogen preparations, including Premarin but is not the major ingredient (Premarin consists of hundreds of estrogen derivatives due to its natural source...pregnant mare urine.
Contraindications
Estradiol should not be given to women who are pregnant or are breastfeeding, women with unexplained uterine bleeding, certain forms of cancer, or prone to blood clotting disorders. The medication is to be kept away from children. Detailed prescription information is available <ref>Estrace/Estradiol patient information leaflet - Warner Chilcott (manufacturer)</ref>
Side effects
Side effects of estradiol therapy may include uterine bleeding, breast tenderness, nausea and vomiting, chloasma, cholestasis, and migraine headaches.
References
PUBCHEM (5757)
Generally refers to the 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. In humans, it is produced primarily by the cyclic ovaries and the PLACENTA. It is also produced by the adipose tissue of men and postmenopausal women. The 17-alpha-isomer of estradiol binds weakly to estrogen receptors (RECEPTORS, ESTROGEN) and exhibits little estrogenic activity in estrogen-responsive tissues. Various isomers can be synthesized.
Therapeutic Indications
- Menopause
- Osteoporosis
KEGG Database(C00951,D00105) Pathway Androgen and estrogen metabolism Prostate cancer
NEXT BIO Database
| MMDB ID | PDB ID | Reference |
|---|---|---|
| 14139 | 1QKT | Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras DCrystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonismJ. Biol. Chem. v276, p.15059-15065 |
| 14140 | 1QKU | Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras DCrystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonismJ. Biol. Chem. v276, p.15059-15065 |
| 17807 | 1JGL | Lamminmaki U, Kankare JACrystal structure of a recombinant anti-estradiol Fab fragment in complex with 17beta -estradiolJ. Biol. Chem. v276, p.36687-36694 |
| 18390 | 1G50 | Eiler S, Gangloff M, Duclaud S, Moras D, Ruff MOverexpression, purification, and crystal structure of native ER alpha LBDProtein Expr. Purif. v22, p.165-173 |
| 18412 | 1JNN | Monnet C, Bettsworth F, Stura EA, Le Du MH, Menez R, Derrien L, Zinn-Justin S, Gilquin B, Sibai G, Battail-Poirot N, Jolivet M, Menez A, Arnaud M, Ducancel F, Charbonnier JBHighly specific anti-estradiol antibodies: structural characterisation and binding diversityJ. Mol. Biol. v315, p.699-712 |
| 20338 | 1GWR | Warnmark A, Treuter E, Gustafsson JA, Hubbard RE, Brzozowski AM, Pike ACInteraction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor alphaJ. Biol. Chem. v277, p.21862-21868 |
| 20905 | 1LHU | Grishkovskaya I, Avvakumov GV, Hammond GL, Catalano MG, Muller YASteroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformationJ. Biol. Chem. v277, p.32086-32093 |
| 25056 | 1PCG | Leduc AM, Trent JO, Wittliff JL, Bramlett KS, Briggs SL, Chirgadze NY, Wang Y, Burris TP, Spatola AFHelix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactionsProc. Natl. Acad. Sci. U. S. A. v100, p.11273-11278 |
| 35805 | 2D06 | Gamage NU, Tsvetanov S, Duggleby RG, McManus ME, Martin JLThe structure of human SULT1A1 crystallized with estradiol. An insight into active site plasticity and substrate inhibition with multi-ring substratesJ. Biol. Chem. v280, p.41482-41486 |
| 43057 | 2J7X | Structure Of Estradiol-Bound Estrogen Receptor Beta Lbd In Complex With Lxxll Motif From Ncoa5.
Pike ACW, Brzozowski AM, Hubbard RE, Walton J, Bonn T, - A, Thorsell G, Engstrom O, Ljunggren J, Gustaffson J-A, Carlquist M, 2006/10/17 |
| 47760 | 1A52 | Tanenbaum DM, Wang Y, Williams SP, Sigler PBCrystallographic comparison of the estrogen and progesterone receptor's ligand binding domainsProc. Natl. Acad. Sci. U. S. A. v95, p.5998-6003 |
| 47957 | 1AQU | Kakuta Y, Pedersen LG, Carter CW, Negishi M, Pedersen LCCrystal structure of estrogen sulphotransferaseNat. Struct. Biol. v4, p.904-908 |
| 49701 | 1IOL | Azzi A, Rehse PH, Zhu DW, Campbell RL, Labrie F, Lin SXCrystal structure of human estrogenic 17 beta-hydroxysteroid dehydrogenase complexed with 17 beta-estradiolNat. Struct. Biol. v3, p.665-668 |
| 55024 | 1A27 | Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152 |
| 56114 | 1FDS | Breton R, Housset D, Mazza C, Fontecilla-Camps JCThe structure of a complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitorsStructure v4, p.905-915 |
| 56115 | 1FDT | Breton R, Housset D, Mazza C, Fontecilla-Camps JCThe structure of a complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitorsStructure v4, p.905-915 |
| 56116 | 1FDW | Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152 |
| 60515 | 2OCF | Rajan SS, Kuruvilla SM, Sharma SK, Kim Y, Huang J, Koide A, Koide S, Joachimiak A, Greene GL, 2006/12/20 |
| 8897 | 1ERE | Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist MMolecular basis of agonism and antagonism in the oestrogen receptorNature v389, p.753-758 |
| Physical Property | Value | Units | Temp (deg C) | Source |
|---|---|---|---|---|
| Melting Point | 178.5 | deg C | EXP | |
| log P (octanol-water) | 4.01 (none) | EXP | ||
| Water Solubility | 3.6 | mg/L | 27 | EXP |
| Vapor Pressure | 1.26E-08 | mm Hg | 25 | EST |
| Henry's Law Constant | 3.64E-11 | atm-m3/mole | 25 | EST |
| Atmospheric OH Rate Constant | 1.23E-10 | cm3/molecule-sec | 25 | EST |
| Organism | Test Type | Route | Reported Dose (Normalized Dose) | Effect | Source |
|---|---|---|---|---|---|
| rat | LD | subcutaneous | > 300mg/kg (300mg/kg) | Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 26, Pg. 740, 1995. |
| 4 | 3 | 2 | 1 | 0 |
|---|---|---|---|---|
| GOOD | INDETERMINATE | INDETERMINATE | INDETERMINATE | POOR |
Reference Article Ref1 Virtual and biomolecular screening converge on a selective agonist for GPR30
Cristian G Bologa1,7, Chetana M Revankar2,3,7, Susan M Young3, Bruce S Edwards3,4, Jeffrey B Arterburn5, Alexander S Kiselyov6, Matthew A Parker6, Sergey E Tkachenko6, Nikolay P Savchuck6, Larry A Sklar3,4, Tudor I Oprea1 & Eric R Prossnitz2,3
Estrogen is a hormone critical in the development, normal physiology and pathophysiology1 of numerous human tissues2. The effects of estrogen have traditionally been solely ascribed to estrogen receptor alpha (ERalpha) and more recently ERbeta, members of the soluble, nuclear ligand–activated family of transcription factors3. We have recently shown that the seven-transmembrane G protein–coupled receptor GPR30 binds estrogen with high affinity and resides in the endoplasmic reticulum, where it activates multiple intracellular signaling pathways4. To differentiate between the functions of ERalpha or ERbeta and GPR30, we used a combination of virtual and biomolecular screening to isolate compounds that selectively bind to GPR30. Here we describe the identification of the first GPR30-specific agonist, G-1 (1), capable of activating GPR30 in a complex environment of classical and new estrogen receptors. The development of compounds specific to estrogen receptor family members provides the opportunity to increase our understanding of these receptors and their contribution to estrogen biology.
Ref2 Drugs Fut 2006, 31(1): 65 ISSN 0377-8282 Copyright 2006 Prous Science CCC: 0377-8282 DOI: 10.1358/dof.2006.031.01.959122
Structure-function similarity between vitamin D3 and estrogens: Scope for effective drug design for vitamin D3 and estrogen dependent disorders Ray, S., Gupta, A.
Vitamin D3 and estradiol are essential hormones that are formed in the body from the same source cholesterol. Whereas vitamin D3 is required mainly for calcium regulation and bone formation, estradiol regulates the reproductive cycle in women and maintains female characteristics. Both hormones are involved in various other functions in the body and act through their respective receptors which belong to the nuclear receptor superfamily. This article discusses the major role of vitamin D3 and estradiol in disorders such as osteoporosis, cancer and calcium regulation. Their functional similarity may be due to their participation at different junctures of the same mechanistic pathway or else a crosstalk between the two hormones and their opposite receptors. This suggests the possibility of designing effective drugs that would interact with both vitamin D3 and estrogen receptors for the treatment of vitamin D3 and estrogen-dependent disorders.
