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gonadal hormones and inhibitors to produce
- 1. The gonadal hormones andinhibitors Estrogens and progestins Androgens
- 2. Neurohormonal control ofthe female reproductive system
- 3. The Menstrual Cycle Copyright© Pearson Education 2010
- 5. • Symptoms of menopause •Hot flushes and sweats • Sleep disturbances • Vaginal dryness • Urinary symptoms • Mood changes • Loss of libido • Osteoporosis and CVD and stroke risk increase
- 6. DRUGS AFFECTING THESEX HORMONE Female sex hormones Hormonal control of the reproductive system in men and women involves sex steroids o They are released from gonads (Estrogen, Progestins, human chorionic gonadotrophin…) hypothalamus (GnRH) and anterior pituitary (FSH & LH). o FSH is the main hormone stimulating oestrogen release o LH stimulates ovulation at midcycle and is the main hormone controlling subsequent progesterone secretion o Oestrogen controls the proliferative phase of the endometrium and has negative feedback effects on the anterior pituitary o Progesterone controls the later secretory phase and has a negative feedback effects on both hypothalamus and anterior p o After implantation, human chorionic gonadotrophin from the chorion becomes important, and later in pregnancy progesterone and other hormones are secreted by the placenta.
- 7. Estrogens Includes:- • Steroidal natural: estradiol, estrone.estriol oSynthesised by the ovary and placenta, and in small amounts, by the testis and adrenal cortex • Steroidal synthetic : ethynyl estradiol ,mestranol,quinestrol ,dienestrol,benzestrol,hexest rol,methestrol • Non steroidal synthetic : diethylstilbestrol, chlorotrianisene, methallenestril • * Premarin - a preparation of conjugated estrogens (sulfate esters of estrone & equilin) • - obtained from pregnant mare’s urine
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- 9. Functions of oestrogens As with other steroids, oestrogen binds to intracellular receptors There are at least two types of oestrogen receptor (ERa and ERb) Binding of estrogen to these receptors alters pattern of gene transcription (stimulation or inhibition) Oestrogen acts in concert with progesterone Estrogen induces synthesis of progesterone receptors in uterus, vagina, anterior pituitary and hypothalamus Progesterone, however, decreases oestrogen receptor expression!!
- 10. Female maturation oE is required for normal growth and maturation of girls: development of genitals and secondary sexual chxs, accelerated growth phase and the closing of the epiphyses of the long bones,… Endometrial Effects o Oestrogen are responsible for the proliferative phase of endometrial regeneration, which occurs from day 5 or 6 until midcycle o Continuous exposure to estrogens for prolonged periods leads to hyperplasia of the endometrium that is usually associated with abnormal bleeding patterns
- 11. Metabolic Effects oMaintenance of the normal structure and function of the skin (collagen) and blood vessels in women o Estrogen also decreases the rate of resorption of bone ( antagonizing osteoclasts!!) o Increases plasma concentrations of HDL(beneficial) LDL Effect on blood coagulation o Oestrogen increase the coagulation of blood ( risk of thromboembolism at high doses) o Increases levels of factors II, VII, IX and X and decreases antithrombin III Other effects o Estrous behavior o Retention of sodium and water by the kidney
- 12. • Effects ofexogenous oestrogen depend on the state of sexual maturity when the oestrogen is administered: in primary hypogonadism: oestrogen stimulates development of secondary sexual characteristics and accelerates growth in adults with primary amenorrhoea: oestrogen, given cyclically with a progestogen, induces an artificial cycle in sexually mature women: oestrogen (with a progestogen) is contraceptive at or after the menopause: oestrogen replacement prevents menopausal symptoms and bone loss. Sex hormones cont… 09/10/2025 12
- 13. Clinical uses ofoestrogens Replacement therapy: primary ovarian failure (e.g. Turner’s syndrome), Treatment of menopausal symptoms or for postmenopausal replacement therapy Contraception Prostate cancer Combined with progestins for intractable dysmenorrhea, hirusutism (wajiga timo ku yeelato), acne and amenorrhea Un wanted effects Tenderness in the breast, nausea, vomiting, anorexia, retention of salt and water with resultant oedema Increased risk of thromboembolism (avoid cardio problem) Menstrual like bleeding when used for post menopausal replacement therapy Feminization if given to males
- 14. Un wanted effects……… •hyper pigmentation • Hypertension and breast tenderness • Cervical or vaginal adenocarcinoma among the daughters of women who took the drug during early pregnancy. E.g. diethylstilbestrol • Post-menopausal uterine bleeding • Small increase in the incidence of breast cancer • Increased risk of endometrial carcinoma if taken alone but concomitant use with progestin prevents this increased risk
- 15. Contraindications • Estrogen dependentneoplasmas such as carcinoma of the endometrium and breast • Undiagnosed genitial bleeding • Liver desease • History of thromboembolic disorder • Heavy smokers
- 16. Antiestrogens • Clomiphene • actsas a partial estrogen agonist and interferes with the negative feed back effects of estrogen on the anterior pituitary!(increase FSH&LH • Used to induce ovulation in treating-infertility • Clomiphene citrate 50mg; oral initially 50mg daily for 5 days, starting on day 3 – 5 of the menstrual cycle or after an induced bleed. • If ovulation is confirmed but conception fails, the same dose may be repeated during the next cycle. If ovulation fails, the dose may be increased to 100 mg daily (as a single dose) for 5 days. • Tamoxifen • Has antioestrogenic action on mammary tissue but oestrogenic actions on plasma lipids • Used for treatment of estrogen sensitive breast cancer! • Raloxifen (selective estrogen modulator) • Use-approved only for the preventive treatment of osteoporosis in postmenopausal women
- 17. PROGESTIN Natural: Progesterone-synthesized in the ovary, testis, and adrenal Synthetic: Hydroxyprogesterone caproate, Medroxyprogesterone acetate, Megestrol acetate, Dimethisterone, Desogestrel, Norethynodrel, Norethindrone.. Physiological Effects Similar to that of other steroid hormones (bind to progesterone receptors and affect gene transcriptions) It promotes the development of a secretory endometrium for a newly forming embryo High level of progesterone that are released during the luteal phase inhibits production of gonadotropin, hence ovulation
- 18. Has littleeffect on protein metabolism, stimulates lipoprotein lipase activity(favor fat deposition), CHO metabolism affected markedly o Progesterone increases basal insulin levels and the insulin response to glucose and promote glycogen storage Progesterone can compete with aldosterone receptor of the renal tubule, ( decrease Na reabsorption) Progesterone is responsible for the alveolobular development of the secretory apparatus in the breast
- 19. Clinical usesof progestins o Hormone replacement therapy o Hormonal contraception, o Luteal-phase to treat infertility & premature labor (dec. contr o Dysmenorrhea, endometriosis. Unwanted effects o Weak androgenic action o Fluid retention, weight gain, hirsutism, acne ( those for androgen likes e.g norethindrone, norgestrel, levonorgestrel, avoid women with acne& use norgestimate, drospirenone… ) o depression, change in libido, Antiprogestins o Mifepristone (partial agonist) o It is used as a medical termination of pregnancy (abortion) in combination with misoprostol
- 20. ANDROGENS Naturalandrogen: testosterone-synthesized mainly by the interstitial cells of the testis (smaller amounts by the ovaries and adrenal cortex) Adrenal production of androgen is under the control of adrenocorticotrophic hormone (ACTH) Synthetic: Testosterone enanthate, testosterone proprionate, testosterone undecanoate and mesterolone Physiological actions Responsible for development of male secondary sexual characteristics and masculination in women
- 21. Androgens Androgens include • Testesteronecypionate • Danazol • Fluoxymesterone • Nandrone • Stanozolol • Methandrostenolone (methandienone) • Oxymetholone • Ethylestrenol • Oxandrolone • Dromostanolone
- 22. Clinical uses Replacementtherapy in testicular failure (male hypogonadism) Anabolic (enhancement of athletic performance) e.g nandrolone, stanozolol Endometriosis e.g danazol Unwanted effects Infertility ( gonadotrophin release negatively!) salt and water retention (edema) Androgens impair growth in children ( via premature fusion of epiphyses) and cause acne and masculinisation in girls
- 23. Andti-androgens • Cyproterone acetate •Finasteride • Flutamide • leuprolide Therapeutic uses • Used as part of the treatment of the prostatic cancer - flutamide, • To treat hirsutism and acne in females –cyproterone • Benign prostatic hypertrophy – finasteride • effective in the treatment of prostate cancer, endometriosis, and precocious puberty - leuprolide
- 24. Hormonal contraception Includes • Oral •Parenteral and • Implanted contraception • Oral contraceptives 1. The combined pill (estrogen with progestin) 2. Progestin only pill
- 25. The combined pill •Most commonly used • Estrogen- ethinylestradiol , mestranol • Progestin- norethindrone , levonorgestrel , desogestrel • The combined pill is taken for 21 consecutive days followed by 7 pill-free days of placebo • One tablet daily for 21 days starting on fifth day of menstruation , then 7 tablet free days or sometimes it has 7 tab of iron preparation • Withdrawal bleeding occurs during the hormone-free interval
- 26. DRUGS USED FORCONTRACEPTION Oral contraceptives Two types Combination of an oestrogen with a progestogen ( the combined pill Progestogen alone (the progestogen only pill) The combined pill The combined oral contraceptive pill is extremely effective Estrogen in most combined preparations is ethinylestradiol The progestogen used in combination: norethisterone, levonorgestrel
- 27. The modeof action could be Oestrogen inhibits secretion of FSH (negative feedback) Progestogen inhibits secretion of LH and thus prevents ovulation it also makes the cervical mucus less suitable for the passage of sperm Oestrogen and progestogen act in concert to alter the endometrium (discourage implantation) This combined pill is taken for 21 consecutive days followed by 7 pill-free days Common adverse effects Weight gain (due to fluid retention or an anabolic effect or b Mild nausea, depression or irritability (mood changes) Skin changes (e.g acne and/ or an increase in pigmentation) Increased risk of thrombo-embolism Amenorrhoea of variable duration on cessation of taking pill
- 28. Contraindications • Cerebrovascular andthromboembolic disease • Estrogen-dependent neoplasms (e.g. genitial tract malignancies) • Liver disease • Migrane Drug interactions • Anticonvalsants ,hypnotics , antibiotics ,antacids,anticoagulants,antidepressants ,steroids and hypoglycemic agents
- 29. Progestogen-only pill The progestogens commonly used are: Norethindrone, Levonorgestrel, Ethynodiol The mode of action is primarily on the cervical mucus (made inhospitable to sperm) Also hinders implantation through is effect on the endometrium and on the motility and secretion of the fallopian tube Are less effective than the combination pill The pills are taken daily without interruption Other contraceptive regimens Long acting progestogen only: Medroxyprogesterone (150 mg i.m with in first 5 days of the cycle repeated every 3 months), Levonorgestrel (sc) Postcoital (Emergency) contraceptives: Oral norgestrel (alone or with oestrogen; is effective if taken within 72 hours coitus) or levonorgestrel (postpill)
- 30. An advantage ofprogestin-only pill can be taken after parturition, as unlike estrogen – containing pills,it does not interfere with lactation Indicated in case of estrogen contraindication as in lactating mothers, diabetics, hypertensive,hepatic disease, psychosis or mental retardation or prior thromboembolism • Preparation • Lynestrenol 0.5mg/day
- 31. Implants • Levonorgesterel (norplant):in six silastic capsules implanted in the left upper arm under local anesthesia,effective up to five years • Disadvantage: need for surgical insertion and removal of capsules Side effects • Irregular menstural bleeding • Headache or visual disturbance • A levonorgestrel –impregnated intrauterine device : has contraceptive action for 3-5 years
- 34. Some Available OralContraceptives 09/10/2025 34
Editor's Notes
- #1 At the beginning of each cycle, a variable number of follicles (vesicular follicles), each containing an ovum, begin to enlarge in response to FSH. After 5 or 6 days, one follicle, called the dominant follicle, begins to develop more rapidly. The outer theca and inner granulosa cells of this follicle multiply and, under the influence of LH, synthesize and release estrogens at an increasing rate. The estrogens appear to inhibit FSH release and may lead to regression of the smaller, less mature follicles. The mature dominant ovarian follicle consists of an ovum surrounded by a fluid-filled antrum lined by granulosa and theca cells. The estrogen secretion reaches a peak just before midcycle, and the granulosa cells begin to secrete progesterone. These changes stimulate the brief surge in LH and FSH release that precedes and causes ovulation
- #2 FSH changes primary follicle into secondary follicle ;grafian follicle/; fluid filled cavity/ mature follicle ( theca cells secrete androgen & granulosa cells converts it estrogen)
- #5 Urinary incontinence is more likely to be due to mechanical factors, such as obesity, gynaecological surgery, or multiparity, than to be associated with the menopause [Sherburn et al, 2001]. Mood changes, including anxiety, irritability, and depression, have been associated with the menopause. These symptoms are more likely to be associated with past problems and life stresses than to be due to the menopause alone. General population studies suggest that most women do not experience major changes in mood during the menopause transition [Hickey et al, 2005; Nelson et al, 2005; Rees and Purdie, 2006a; Roberts, 2007]. Exclude depression. Cognitive disturbance, such as forgetfulness or difficultly concentrating. Cross-sectional studies suggest that these symptoms are unlikely to be related to the menopause [Nelson et al, 2005]. Loss of libido can be attributed to androgen deficiency. However, non-hormonal factors, such as conflict between partners, insomnia, inadequate stimulation, life stresses, or depression, are also important contributors and should not be overlooked [Rees and Purdie, 2006a]. Muscle and joint pains. Pain and swelling resulting in restriction of mobility most often affects the small joints of the hands and feet, as well as the knees, elbows, and the cervical spine. These symptoms have been linked to a decrease in oestrogen, but osteoarthritis, rheumatoid arthritis, and mechanical trauma are common causes [Panay et al, 2004; Lauritzen and Studd, 2005]. Skin changes. Soon after the menopause, skin collagen content and skin thickness decrease, and skin laxity and wrinkling increase abruptly. Skin elasticity also decreases. It is difficult to separate age-related skin changes, smoking, and sun exposure from changes related to declining hormonal secretion and menopause [SOGC, 2006]. Weight gain is unlikely to be due to the perimenopause or the menopause. Body weight in women tends to increase with age, especially beginning at or near the menopause. The average weight gain ranges from 2.25–4.19 kg. Body fat redistribution to the abdomen also occurs with age (independently of weight gain). This centralized abdominal fat distribution is an independent risk factor for cardiovascular disease in women [SOGC, 2006]. A longitudinal study of 418 women found that weight gain was more likely to be due to alcohol consumption and lack of exercise
- #7 Estradiol is the most potent and major secretory product of the ovary For hormone replacement therapy, contracelptives, hypogonadism
- #9 e.G stimulate breast, bone, endometrium… inhibit osteoblasts…
- #10 Endometrial effect: continuous exposure to estrogens for prolonged periods leads to hyperplasia of the endometrium that is usually associated with abnormal bleeding patterns
- #11 Pharmacological effects Female sexual maturation, Endometrial effect: continuous exposure to estrogens for prolonged periods leads to hyperplasia of the endometrium that is usually associated with abnormal bleeding patterns;Metabolic and cardiovascular effects It decreases the rate of resorption of bone Causes some degree of retention of salt and water The conc of serum triglycerides and of HDL is raised, whereas that of LDL is decrease It increase the coagulability of the blood
- #13 Primary Hypogonadism Estrogens have been used extensively for replacement therapy in estrogen-deficient patients. The estrogen deficiency may be due to primary failure of development of the ovaries, premature menopause, castration, or menopause. Treatment of primary hypogonadism is usually begun at 11–13 years of age in order to stimulate the development of secondary sex characteristics and menses, to stimulate optimalgrowth, to prevent osteoporosis and to avoid the psychological consequences of delayed puberty and estrogen deficiency. Treatment attempts to mimic the physiology of puberty. Many preparations (oral, transdermal, intramascular, implantable and topical) are available
- #14 Estrogen causes over production of melanin
- #16 Tamoxifen- used to palliate (to reduce violence of a disease) oestrogen-sensitive breast cancer Clomiphene- used to induce ovulation in treating infertility They compete with natural estrogen for receptors in target organs Raloxifen- partial agonists Dose and Administration: Oral: Adult: initially 50 mg daily for 5 days, starting on day 3 - 5 of the menstrual cycle or after an induced bleedDose and Administration: Oral: Adult: initially 50 mg daily for 5 days, starting on day 3 - 5 of the menstrual cycle or after an induced bleed. If ovulation is confirmed but conception fails, the same dose may be repeated during the next cycle. If ovulation fails, the dose may be increased to 100 mg daily (as a single dose) for 5 days.
- #17 T he major uses of progestational hormones are for hormone replacement therapy (see above) and hormonal contraception (see below). In addition, they are useful in producing long-term ovarian suppression for other purposes. When used alone in large doses parenterally (eg, medroxyprogesterone acetate, 150 mg intramuscularly every 90 days), prolonged anovulation and amenorrhea result. This therapy has been employed in the treatment of dysmenorrhea, endometriosis, and bleeding disorders when estrogens are contraindicated, and for contraception.
- #18 If conception takes place, progesterone continues to be secreted, maintaining the endometrium in a favorable state for the continuation of the pregnancy and reducing uterine contractions. If conception does not take place, the release of progesterone from the corpus luteum ceases abruptly. This decline stimulates the onset of menstruation. Figure 26.6 summarizes the hormones produced during the menstrual cycle. Progesterone has little effect on protein metabolism. It stimulates lipoprotein lipase activity and seems to favor fat deposition. The effects on carbohydrate metabolism are more marked. Progesterone increases basal insulin levels and the insulin response to glucose. There is usually no manifest change in carbohydrate tolerance. In the liver, progesterone promotes glycogen storage, possibly by facilitating the effect of insulin. Progesterone also promotes ketogenesis.
- #19 Progestins that are derived from 19-nortestosterone (for example, norethindrone, norethindrone acetate, norgestrel, levonorgestrel) possess some androgenic activity because of their structural similarity to testosterone and can cause acne and hirsutism. Less androgenic progestins, such as norgestimate and drospirenone, may be preferred in women with acne :: clinical uses Secondary amenorrhea,uterine bleeding disorders,luteal-phase support to treat infertility and premature labor (inhibit contraction)
- #20 Ant-progestin Mifepristone [mih-feh-PRIH-stone] (also designated as RU-486) is a progesterone antagonist with partial agonist activity. Administration of this drug to females early in pregnancy usually results in abortion of the fetus due to interference with the progesterone needed to maintain pregnancy. Mifepristone is often combined with the prostaglandin analog misoprostol (administered orally or intravaginally) to induce uterine contractions. The major adverse effects are significant uterine bleeding and the possibility of an incomplete abortion.
- #23 Pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus is essential for the release of the gonadotropins folliclestimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. However, continuous administration of GnRH inhibits gonadotropin release through down-regulation of the GnRH receptors on the pituitary. Continuous administration of synthetic GnRH analogs, such as leuprolide [loo-PROE-lide], goserelin [GOE-se-rel-in], nafarelin [NAFF-a-rel-in], and histrelin [his-TREL-in], is effective in suppressing production of the gonadotropins (Figure 24.5). [Note: Several of these agents are available as implantable formulations that provide convenient continuous delivery of the drug.] Suppression of gonadotropins, in turn, leads to reduced production of gonadal steroid hormones (androgens and estrogens). Thus, these agents are effective in the treatment of prostate cancer, endometriosis, and precocious puberty
- #25 One tablet daily for 21 days starting on fifth day of menstruation , then 7 tablet free days or sometimes it has 7 tab of iron preparation or
- #26 Progesterone by itself is not used widely as a contraceptive therapy because of its rapid metabolism, resulting in low bioavailability. Synthetic progestogens (that is,progestins) used in contraception are more stable to firstpass metabolism, allowing lower doses when administered orally Oral medroxyprogesterone acetate has a half-life of 30 days. When injected intramuscularly or subcutaneously, it has a half-life of about 40 to 50 days and provides contraceptive activity for approximately 3 months. The other progestins have half-lives of 1 to 3 days, allowing for once-daily dosing.
- #27 HOT FLUSH: Feeling of intense heat over the trunk and face, with skin flushing and sweating May begin before menses cease permanently Thought to result from increasing pulsatile release of GnRH from the hypothalamus, thereby affecting the nearby temperature-regulating area in the brain More pronounced late in the day, during hot weather, periods of tension, or after ingesting hot foods/drinks
- #29 Mechanism Primarily on the cervical mucus which is made inhospitable to sperm Also hinders implantation through is effect on the endometrium and on the motility and secretion of the fallopian tube Injectables Medroxyprogesterone acetate: 150 mg deep IM injection with in the first 5 days of the cycle to be repeated every 3 months After a 150 mg dose,ovulation is inhibited for at least 14 weeks
- #32 Formulation: a) low estrogen, low progesterone(0.03mg ethinylestradiol+0.15 mg norgestril b) Low esterogen, high progestogen (0.03 mg ethinylestradiol + 1.5 mg norethindrone) c) High estrogen, high progestrone (0.05 mg ethinylestradiol + 0.5 mg norgestril)