Download presentation
Presentation is loading. Please wait.
1
Estrogens and Progestins
2
Introduction Estrogens and progestins are endogenous hormones that produce numerous physiological actions The therapeutic use of estrogens and progestins largely reflects extensions of their physiological activities The most common uses of these agents are menopausal hormone therapy and contraception in women In women, these include developmental effects, neuroendocrine actions involved in the control of ovulation, the cyclical preparation of the reproductive tract for fertilization and implantation, and major actions on mineral, carbohydrate, protein, and lipid metabolism Estrogens also have important actions in males, including effects on bone, spermatogenesis, and behavior
3
Introduction Estrogen- and progesterone-receptor antagonists also are available The main uses of anti-estrogens are treatment of hormone-responsive breast cancer and infertility The main use of anti-progestins has been for medical abortion
4
- - - - + + + NE Hypothalamus GnRH FSH LH Target Tissues
DA, Opioid, GABA NE + Hypothalamus + GnRH - - Anterior pitutary gland - FSH LH + Ovaries Estrogen Progesterone Target Tissues
5
Estrogens
6
Estrogens The most potent endogenous estrogen is estradiol, followed by estrone & estriol Preparations of conjugated estrogens containing sulfate esters of estrone and equilin estrogens (equilenin & equilin) obtained from pregnant mares’ urine Ethinyl substitutions at the C17 position of estradiol (ethinyl estradiol) greatly increase oral potency by inhibiting first-pass hepatic metabolism
7
Estrogens Steroidal estrogens arise from androstenedione or testosterone by aromatization. The reaction is catalyzed by aromatase (CYP19) In postmenopausal women, the principal source of circulating estrogen is adipose tissue stroma, where estrone is synthesized from dehydroepiandrosterone secreted by the adrenals The placenta uses fetal dehydroepiandrosterone and its 16-hydroxyl derivative to produce large amounts of estrone and estriol
8
Cholesterol Progesterone DHEA Aromatase Androstenedione Estrone Estriol Aromatase Testosterone Estradiol
9
Estrogen pharmacokinetics
Estradiol is extensively bound to SHBG Estradiol is converted primarily by the liver to estrone and estriol, the major urinary metabolite Estradiol undergo enterohepatic recirculation via (1) sulfate and glucuronide conjugation in the liver, (2) biliary secretion of the conjugates into the intestine, and (3) hydrolysis in the gut (largely by bacterial enzymes) followed by reabsorption
10
Estrogen preparations
For many uses, preparations are available as an estrogen alone or in combination with a progestin All of the estrogens produce almost the same hormonal effects, their potencies vary both between agents and depending on the route of administration
11
Estrogen preparations
Oral administration is common and may utilize estradiol, conjugated estrogens, esters of estrone and other estrogens, and ethinyl estradiol Tansdermal patches provides slow, sustained release of the hormone, systemic distribution, and more constant blood levels than oral dosing Estradiol and conjugated estrogen creams also are available for topical administration to the vagina Mixtures of conjugated estrogens prepared from plant-derived sources. These are hydrolyzed by enzymes present in the lower gut that remove the charged sulfate groups and allow absorption of estrogen across the intestinal epithelium
12
Commonly Used Estrogens Preparation Average Replacement Dosage
Ethinyl estradiol 0.005–0.02 mg/d Micronized estradiol 1–2 mg/d Estradiol cypionate 2–5 mg every 3–4 weeks Estradiol valerate 2–20 mg every other week Estropipate 1.25–2.5 mg/d Conjugated, esterified, or mixed estrogenic substances: Oral 0.3–1.25 mg/d Injectable 0.2–2 mg/d Transdermal Patch Quinestrol 0.1–0.2 mg/week Chlorotrianisene 12–25 mg/d Methallenestril 3–9 mg/d
13
Physiological effects
Growth and Development Neuroendocrine Control of the Menstrual Cycle Endometrial Effects
14
Physiological effects
Metabolic Effects: Decrease bone resorption rate Increase HDL levels and a slight decrease in LDL , a reduction in total plasma cholesterol, and a slight increase in TG levels Increase plasma levels of CBG, TBG, & SHBG Enhance the coagulability of blood: increase circulating levels of factors II, VII, IX, and X and decrease antithrombin III
15
Therapeutic uses of estrogens
Menopausal Hormone therapy (MHT) Benefits of estrogen therapy include amelioration of vasomotor symptoms and the prevention of bone fractures and urogenital atrophy MHT with estrogens should use the lowest dose and shortest duration necessary to achieve an appropriate therapeutic goal
16
Therapeutic uses of estrogens
Menopausal Hormone therapy (MHT) Optimal management of the postmenopausal patient requires careful assessment of her symptoms as well as consideration of her age and the presence of (or risks for) cardiovascular disease, osteoporosis, breast cancer, and endometrial cancer ERT in postmenopausal women is associated with an increased incidence of endometrial carcinoma; this led to the use of HRT to reduces the risk of this cancer
17
Therapeutic uses of estrogens
Menopausal Hormone therapy (MHT) For women who have undergone a hysterectomy, endometrial carcinoma is not a concern, and it is most prescribe estrogen (conjugated estrogens or ethinyl estradiol) Oral estrogen should be avoided in women with hypertriglyceridemia, liver disease, and gallbladder disease. For these women, transdermal administration is a safer approach
18
Therapeutic uses of estrogens
Menopausal Hormone therapy (MHT) Vasomotor symptoms: hot flashes may alternate with chilly sensations, inappropriate sweating, and (less commonly) paresthesias Treatment with estrogen is specific and is the most efficacious pharmacotherapy for these symptoms Without treatment, hot flushes in most women typically disappear within 1 to 2 years, but in some untreated women hot flushes continue for more than 20 years
19
Therapeutic uses of estrogens
Menopausal Hormone therapy (MHT) Osteoporosis: Osteoporosis is an indication for estrogen therapy, which clearly is efficacious in decreasing the incidence of fractures Estrogens are most effective if treatment is initiated before significant bone loss occurs, and their maximal beneficial effects require continuous use; bone loss resumes when treatment is discontinued
20
Therapeutic uses of estrogens
Menopausal Hormone therapy (MHT) Vaginal dryness and urogenital atrophy: These include dryness and itching of the vagina, dyspareunia, swelling of tissues in the genital region, pain during urination, a need to urinate urgently or often, and sudden or unexpected urinary incontinence When estrogens are being used solely for relief of vulvar and vaginal atrophy, local administration as a vaginal cream, ring device, or tablets may be considered
21
Therapeutic uses of estrogens
Menopausal Hormone therapy (MHT) Cardiovascular events Epidemiological studies consistently showed an association between estrogen use and reduced CV disease in postmenopausal women However, estrogens promote coagulation and thromboembolic events Transdermal or vaginal administration of estrogen may be associated with decreased CV risk
22
Adverse Effects Nausea and vomiting
Breast tenderness: minimized by using the smallest effective dose Postmenopausal uterine bleeding Increased frequency of migrane headache Cholestasis and gallbladder disease
23
Adverse Effects Cancer Increase risk of endometrial cancer
The risk seems to vary with the dose and duration of treatment: 15 times greater in patients taking large doses of estrogen for 5 or more years The concomitant use of a progestin prevents this increased risk and may in fact reduce the incidence of endometrial cancer
24
Selective Estrogen Receptor Modulators (SERMs)
Class of estrogen-related compounds with tissue-selective actions Their pharmacological goal is to produce beneficial estrogenic actions in certain tissues (e.g., bone) but antagonist activity in others (e.g., breast and endometrium)
25
Tissue Dependent Action Selective Estrogen Receptor Modulator
Source: Tissue Dependent Action Review: Selective Estrogen Receptor Modulator (SERM) Reviewer Memo: ER Antagonistic Effects (uterus, breast) Tissue Dependent Action Agonistic Effects (bone) Increase BMD and reduce the risk of vertebral fractures ER = Estrogen Receptor BMD = Bone Mineral Density Slide Modified: Memo:
26
Tamoxifen It is a partial estrogen agonist in breast and is used as a palliative treatment and chemopreventative for breast cancer in high-risk women It is a full agonist in bone and endometrium, and prolonged use of tamoxifen leads to a fourfold to fivefold increase in the incidence of endometrial cancer ADEs: nausea, vomiting, hot flushes, & increases the risk of venous thrombosis
27
Estrogen receptor in breast cell blocked
National Cancer Institute Understanding Cancer and Related Topics Understanding Estrogen Receptors, Tamoxifen, and Raloxifene Estrogen Tamoxifen Estrogen receptor in breast cell blocked Estrogen receptor in uterine endometrial cell Breast receptor not activated Uterine receptor activated No breast cell proliferation Endometrial cell proliferation Decreased cancer risk Increased cancer risk NCI Web site:
28
Raloxifene It is an estrogen agonist in bone and is approved for the prevention of osteoporosis in postmenopausal women Like tamoxifen, it has antagonist effects in breast tissue and reduces the incidence of breast cancer in women who are at very high risk Unlike tamoxifen, the drug has no estrogenic effects on endometrial tissue ADEs: hot flushes, leg cramps, & increased risk of DVT
29
Clomiphene Partial estrogen agonist
Interfere with the negative feedback of estrogen on the hypothalamus: GnRH secretion becomes more pulsatile, which results in increased pituitary gonadotropin (FSH, LH) release Uses: Infertility associated with anovulatory cycles Adverse effects: headache, nausea, hot flushes, visual disturbances, & ovarian enlargement Clomiphene binds to estrogen receptors and stays bound for long periods of time. This prevents normal receptor recycling and causes an effective reduction in hypothalamic estrogen receptor number. Since estrogen can no longer effectively feedback on the hypothalamus, GnRH secretion becomes more pulsatile, which results in increased pituitary gonadotropin (FSH, LH) release
30
Estrogen-Synthesis Inhibitors: Aromatase inhibitors
Aromatase is the enzyme required for estrogen synthesis Agents: Irreversible steroidal inhibitors: Exemestane Reversible Non-steroidal inhibitors: anastrozole & letrozole These agents may be used as first-line treatment of breast cancer or as second-line drugs after tamoxifen
31
Cholesterol Progesterone Aromatase Inhibitors Aromatase
DHEA Aromatase Androstenedione Estrone Aromatase Testosterone Estradiol
32
Estrogen-Synthesis Inhibitors: Aromatase inhibitors
Unlike tamoxifen, they do not increase the risk of uterine cancer or VTE ADEs: related to reduce circulating and local levels of estrogens (e.g. hot flushes and significant bone loss)
33
Progestins
34
Progestins Natural progestins: Progesterone
It is secreted by the corpus luteum in the second part of the menstrual cycle, and by the placenta during pregnancy Small amounts are also secreted by testis and adrenal cortex
35
Progestins pharmacokinetics
Progesterone is rapidly absorbed following administration by any route It undergoes rapid first-pass metabolism, with a t1/2 of 5 minutes Progesterone is metabolized primarily in the liver to pregnanediol and its sulfate and glucuronide conjugates are eliminated in the urine
36
Preparations Naturally occurring hormone and its derivatives
They display limited binding to glucocorticoid, androgen, and mineralocorticoid receptors, a property that probably accounts for some of their nonprogestational activities Progesterone undergoes rapid first-pass metabolism, and is orally inactive Other preparations of progesterone are available for oral administration (micronized), intramuscular injection, or administration via the vagina or rectum Hydroxyprogesterone caproate and MPA are available for IM administration
37
Preparations Testosterone derivatives “19-nortestosterones”
Can be given orally These compounds have progestational activity and retain some androgenic activity Norethisterone and norgestrel have androgenic activity Newer progestogens without androgenic activity include desogestrel, norgestimate, and gestodene Newer progestogens without androgenic activity include desogestrel, norgestimate, and gestodene may be considered for women who experience side effects such as acne, depression or breakthrough bleeding with the older drugs. However, these newer drugs have been associated with higher risks of venous thromboembolic disease
38
Properties of Some Progestational Agents.
Route Duration of Action Activities1 Estrogenic Androgenic Antiestrog, Antiandrog. Anabolic Progesterone and derivatives Progesterone IM 1 day – + Hydroxyprogesterone caproate 8–14 days sl Medroxyprogesterone acetate IM, PO Tabs: 1–3 days; injection: 4–12 wks Megestrol acetate PO 1–3 days 17-Ethinyl testosterone derivatives Dimethisterone 19-Nortestosterone derivatives Desogestrel Norethynodrel2 Lynestrenol3 Norethindrone2 Norethindrone acetate2 Ethynodiol diacetate2 L-Norgestrel2 1Interpretation: + = active; – = inactive; sl = slightly active. Activities have been reported in various species using various end points and may not apply to humans. 2See Table 40–3. 3Not available in USA.
39
Effects of Progesterone
Neuroendocrine action: Progesterone produced in the luteal phase of the cycle decreases the frequency of GnRH pulses Reproductive tract: Decrease estrogen-driven endometrial proliferation and induces a secretory endometrium
40
Effects of Progesterone
CNS: Increases basal body temperature Progesterone also may have depressant and hypnotic actions in the CNS
41
Effects of Progesterone
Progesterone stimulates lipoprotein lipase activity and favor fat disposition Increases basal insulin levels and the insulin response to glucose In the liver, it promotes glycogen storage by facilitating the effect of insulin Decreases the plasma levels of many a.as and leads to increased urinary nitrogen excretion Decreases Na+ reabsorption in the kidney
42
Therapeutic uses of Progestins
Hormone replacement treatment: in combination with estrogen for hormone therapy of postmenopausal women Contraception: either alone or with an estrogen Test for estrogen secretion and for responsiveness of the endometrium Decrease the occurrence of endometrial hyperplasia and carcinoma caused by unopposed estrogens
43
Therapeutic uses of Progestins
Treatment of dysmenorrhea , endometriosis, and bleeding disorders when estrogens are contraindicated
44
Adverse Effects Major effects: headache, fluid retention, depression, weight gain, & changes in libido Progestins with androgenic activity (19-nortestosterone derivatives): Plasma lipids: increase LDL and cause either no effect or modest reduction in serum HDL levels Acne Hirsutism
45
Antiprogestin: Mifepristone
It effectively competes with progesterone for binding to PR Mifepristone decreases endogenous progesterone coupled with blockade of progesterone receptors in the uterus increases uterine prostaglandin levels and sensitizes the myometrium to their contractile actions Mifepristone also causes cervical softening, which facilitates expulsion of the detached blastocyst Mifepristone effectively competes with both progesterone and glucocorticoids for binding to their respective receptors
46
Antiprogestin: Mifepristone
Clinical uses: Early termination of pregnancy (abortificant): in combination with misoprostol or other prostaglandins Emergency postcoital contraceptive Control high blood sugar levels (hyperglycemia) in adults with endogenous Cushing’s syndrome ADEs: Prolonged vaginal bleeding (major), abdominal pain, uterine cramps, & NVD Mifepristone effectively competes with both progesterone and glucocorticoids for binding to their respective receptors
47
Selective Progesterone Receptor Modulators (SPRMs)
Exert clinically relevant tissue-selective progesterone agonist, antagonist, or partial (mixed) agonist/antagonist effects on various progesterone target tissues Ulipristal acetate (UPA): approved by FDA in June 2010 for use as an emergency contraceptive SEs: abdominal pain and menstrual disorders (irregular vaginal bleeding, premenstrual syndrome and uterine cramps)
48
Hormonal contraception
49
Types of hormonal contraceptives
Combined hormonal contraceptive Progestin-only contraceptives Postcoital or emergency contraceptives
50
Combined oral contraceptive
The most frequently used agents containing both an estrogen and a progestin Their theoretical efficacy is considered to be 99.9% Combination oral contraceptives are generally provided in 21-day packs with an additional 7 pills containing no active hormone The U.S. Food and Drug Administration today approved Beyaz tablets, an estrogen/progestin combined oral contraceptive that also contains a folate (levomefolate calcium mg)
51
Combined oral contraceptive
The U.S. FDA approved Beyaz tablets, an estrogen/progestin combined oral contraceptive that also contains a folate (levomefolate calcium mg) Further divided into: Monophasic: constant dosage of both components during the cycle Multiphasic: dosage of one or both components is changed during the cycle
52
Multiphasic vs Monophasic Preparations*
18 10 5 1.0 0.75 0.5 0.4 20 Norethindrone (mg) Endogenous progesterone (ng/mL) SLIDE 7 menses Day of pill cycle Monophasic (Ovcon 35) Multiphasic (Ortho Novum 7/7/7) Endogenous progesterone level *Ethinyl estradiol content is constant (35 µg) for both preparations. Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 3rd ed. 1996:1416.
53
Combined oral contraceptive
The estrogen in most combined preparation is ethinyl estradiol, though a few preparations contain mestranol instead Progestins are 19-nor compounds that have varying degrees of androgenic, estrogenic, and antiestrogenic activities that may be responsible for some side effects The most common progestins are norethindrone, norethindrone acetate, norgestrel, levonorgestrel, desogestrel, norgestimate, and drospirenone
54
Combined oral contraceptive
The estrogen content of current preparations ranges from 20µg to 50 µg; most contain µg The dose of progestin is more variable because of differences in potency of the compounds used
55
Combined oral contraceptive
Additional options for combined hormonal contraceptives include: Transdermal patch containing ethinyl estradiol and norelgestromin: applied weekly for 3 weeks. Week 4 is patch-free, and withdrawal bleeding occurs Vaginal ring containing ethinyl estradiol and etonogestrel: is used for 3 weeks. Week 4 is ring-free, and withdrawal bleeding occurs Efficacy, contraindications, and ADEs similar to those of oral contraceptives
56
Mechanism of action Estrogen: inhibits secretion of FSH via negative feedback on the anterior pituitary, and thus suppresses development of the ovarian follicle Progestin: Inhibits secretion of LH and thus prevents ovulation Induces viscous mucus that reduces sperm penetration and induces an endometrium that is not receptive to implantation
57
Clinical uses Contraception
Endometerosis when dysmenorrhoea is the major symptoms: long term treatment with estrogen and progestins
58
Adverse effects Cardiovascular Effect:
Relatively low and is determined by the specific compound and combination used For nonsmokers without other risk factors such as hypertension or diabetes, there is no significant increase in the risk of CV events Oral contraceptives increase the risk of various CV disorders, especially in women ≥35 years who are heavy smokers (with predisposing risk factors) The association with myocardial infarction is thought to involve acceleration of atherogenesis because of decreased glucose tolerance, decreased levels of HDL, increased levels of LDL, and increased platelet aggregation
59
CV Mortality Risk with Smoking & OC Use
Oral contraceptive nonuser Oral contraceptive user Cases per 100,000 Woman-Years Nonsmoker Smoker Nonsmoker Smoker Attributable Risk/100,000 User-Years 0.06 1.73 3.03 19.4 < 35 years of age ≥ 35 years of age Sherif K. Am J Obstet Gynecol. 1999;180(Pt 2):S343-S348.
60
Adverse effects Cardiovascular Effect:
VTE (e.g. PE) : Risk is related to the estrogen but not the progestin content of oral contraceptives Postmarketing epidemiologic studies indicate that women using transdermal contraceptives have a higher than expected exposure to estrogen and are at increased risk for the development of venous thromboembolism The association with myocardial infarction is thought to involve acceleration of atherogenesis because of decreased glucose tolerance, decreased levels of HDL, increased levels of LDL, and increased platelet aggregation
61
Adverse effects Cardiovascular Effect: MI:
The use of oral contraceptives is associated with a slightly higher risk of MI in women who are obese, have a history of preeclampsia or hypertension, or have hyperlipoproteinemia or diabetes The risk depends on the specific composition of the pill used and the patient's susceptibility to the particular effects The association with myocardial infarction is thought to involve acceleration of atherogenesis because of decreased glucose tolerance, decreased levels of HDL, increased levels of LDL, and increased platelet aggregation The progestational component of oral contraceptives decreases HDL cholesterol levels, in proportion to the androgenic activity of the progestin
62
Adverse effects Their ability to induce neoplasms is controversial
Cancer Combined oral contraceptives reduce the risk of endometrial and ovarian cancer. This is due to the inclusion of progestins which opposes estrogen-induced proliferation, throughout the entire 21 days Their ability to induce neoplasms is controversial
63
Adverse effects Metabolic effects:
Weight gain: more common with the combination agents containing androgen-like progestins Serum lipids: Estrogen causes an increase in HDL and a decrease in LDL Progestins antagonize the beneficial effect of estrogen (particularly the 19-nortestosterone derivative) Estrogen-dominant preparations are best for individuals with elevated serum cholesterol
64
Adverse effects Miscellaneous Effects
Nausea, mastalgia, and edema: related to the amount of estrogen Breakthrough bleeding: Occur if the estrogen-to-progestin ratio is too low to produce a stable endometrium May be prevented by switching to a pill with a higher ratio or using biphasic and triphasic oral contraceptives
65
Adverse effects Mild headache and migraine headaches
Increased skin pigmentation, acne, and hirsutism: mediated by the androgenic activity of the 19-nor progestins Cholestatic jaundice & increase the incidence of symptomatic gallbladder disease (e.g. cholecystitis and cholangitis) Amenorrhea in some patients following cessation of administration of oral contraceptives Vaginal infections and bacteriuria
66
Contraindications The presence or history of thromboembolic disease, cerebrovascular disease, MI, CAD, or congenital hyperlipidemia Known or suspected carcinoma of the breast Carcinoma of the female reproductive tract Estrogen-dependent/responsive neoplasias Abnormal undiagnosed vaginal bleeding Pregnancy Past or present liver tumors or impaired liver function Women over 35 years of age who smoke heavily (e.g., >15 cigarettes/day)
67
Drug interactions CYP450 enzyme inducers (e.g. rifampin, barbiturates, and phenytoin): may result in contraceptive failure Antibiotics (e.g. amoxicillin): reduce estrogen enterohepatic recycling and may decrease the effectiveness of oral contraceptives
68
Progestin only contraceptives
Minipills: As effective as combination pills Continuous progestin therapy without concomitant administration of estrogens Agents: norethisterone, levonorgestrel, or ethynodiol Particularly suited for use in patients for whom estrogen administration is undesirable ADEs: irregular bleeding episodes, headache, weight gain, and mood changes
69
Progestin only contraceptives
Progestin Implant A subdermal implant (4-cm capsule) containing etonogestrel offers long-term contraception (~ 2-4 yrs) Low failure rate (does not rely on patient compliance) Progestin intrauterin device A T-shaped levonorgestrel-releasing intrauterine system that provide contraception for up to 5-years
70
Progestin only contraceptives
Medroxyprogesterone acetate (MPA) Administered IM every 3 months Major disadvantage is the prolonged time required in some patients for ovulatory function to return after cessation of therapy It should not be used for patients planning a pregnancy in the near future MPA for contraceptive injection increase the risk of osteoporosis
71
Postcoital or emergency Contraceptives
Should be administered within 72 hours of unprotected intercourse PREVEN (The combined regimen): uses large doses of both estrogen and progestin, taken as two doses seperated by 12-hours PLAN B (Progestin only regimen): two doses of levonorgestrel “minipill” separated by 12 hours A single oral dose of mifepristone followed by a single dose of a prostaglandin (Misoprostol) 48 hours later
72
Postcoital or emergency Contraceptives
Ulipristal acetate (PLAN C): Its efficacy is maintained through a five day period following exposure , making ulipristal a more versatile emergency contraceptive Unlike levonorgestrel, is not approved for over the counter use
73
Postcoital or emergency Contraceptives
Nausea and vomiting are the main untoward effects and may be severe Emergency contraceptives are contraindicated in the case of confirmed pregnancy
74
Choice of Contraceptive Preparations
For a given individual, both the efficacy and side effects of hormonal contraceptives may vary considerably among preparations Risks for serious side effects as enumerated earlier should be considered before initiating contraceptives in any individual patient Treatment should generally begin with preparations containing the minimum dose of steroids that provides effective contraceptive coverage
75
Choice of Contraceptive Preparations
Typically a pill with µg of estrogen, but preparations with 20 µg may be adequate for lighter women or >40 years of age with perimenopausal symptoms In women for whom estrogens are contraindicated or undesirable, progestin-only contraceptives may be an option (e.g., nursing mothers and women >40 years of age, in whom fertility may be decreased) A preparation containing 50 µg of estrogen may be required for heavier women
76
Choice of Contraceptive Preparations
The choice of a preparation also may be influenced by the specific 19-nor progestin component because this component may have varying degrees of androgenic and other activities These side effects are greatly reduced in newer low-dose contraceptives that contain progestins with little to no androgenic activity
77
Noncontraceptive Health Benefits
Significantly reduce the incidence of ovarian and endometrial cancer within 6 months of use, and the incidence is decreased 50% after 2 years of use Depot MPA injections also reduce very substantially the incidence of uterine cancer for up to 15 years after oral contraceptive use is discontinued Decrease the incidence of ovarian cysts and benign fibrocystic breast disease
78
Noncontraceptive Health Benefits
Benefits related to menstruation: more regular menstruation, reduced menstrual blood loss and less iron-deficiency anemia, and decreased frequency of dysmenorrhea Decreased incidence of pelvic inflammatory disease and ectopic pregnancies, and endometriosis
Similar presentations
© 2024 SlidePlayer.com. Inc.
All rights reserved.