Pharmacology of Sex Hormones_7th & 8th Session

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Androgens Progesterone Estrogens

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Pharmacology of Sex Hormones (Progesterone, Estrogens, Testosterones):

Pharmacology of Sex Hormones (Progesterone, Estrogens, Testosterones) Prof. R. K. Dixit Pharmacology & Therapeutics King George’s Medical University Lucknow dixitkumarrakesh@gmail.com

7th Session (Drugs reducing Progestin activity) :

7th Session (Drugs reducing Progestin activity) Anti-progestins Menstrual cycle Contraception Why Types Hormonal type Male contraception

Slide3:

Mifepristone A 19-norsteroid Possess Potent antiprogestational Antiglucocorticoid Antiandrogenic activity

Slide4:

Mifepristone If given during the follicular phase, Antiprogestin action results in attenuation of the midcycle Gn surge Slowing of follicular development Delay/failure of ovulation If given during the luteal phase Prevents secretory changes by blocking progesterone action on endometrium Later in the cycle, it blocks progesterone support to the endometrium Unrestrains PG release Stimulates uterine contractions Sensitizes the myometrium to PGs and induces menstruation If implantation has occurred, it blocks decidualization Conceptus is dislodged, HCG production falls, secondary luteolysis occurs Endogenous progesterone secretion decreases and cervix is softened Lead to ABORTION.

Slide5:

Mifepristone Partial agonist and competitive antagonist at both A and B forms of PR Regarded as ‘progesterone receptor modulator’ The weak agonistic action is not manifest in the presence of progesterone Pharmacokinetics A ctive orally, but bioavailability is only 25% Metabolized in liver by CYP 3A4 and excreted in bile Enterohepatic circulation occurs Interaction With CYP 3A4 inhibitors (erythromycin, ketoconazole) Inducers ( rifampin , anticonvulsants)

Slide6:

Mifepristone Uses Termination of pregnancy of up to 7 weeks : 600 mg as single oral dose 48 hours later by a 400 mg oral misoprostol or ( 1 mg gemeprost pessary ) Accepted nonsurgical method of early first trimester abortion Cervical ripening 24–30 hours before attempting abortion or induction of labour Postcoital contraceptive Mifepristone 600 mg given within 72 hr of intercourse interferes with implantation Once-a-month contraceptive A single 200 mg dose of mifepristone given 2 days after midcycle each month Other proposed uses Endometriosis, uterine fibroid, certain breast cancers and in meningioma, induction of labor , Cushing syndrome

Slide7:

Mifepristone Adverse Effects :- Anorexia, nausea, tiredness, abdominal discomfort , uterine cramps etc Preparations:- T-PILL + MISO: Mifepristone 200 mg (3 tabs) + Misoprostol 200 μg (2 tabs); for medical termination of pregnancy of upto 49 days 3 tablets of T-PILL on day 1, followed on day 3 by 2 tablets of MISO.

Slide8:

Ulipristal ‘selective progesterone receptor modulator’ (SPRM) For use as emergency contraceptive (30mg) Inhibits ovulation by suppressing LH surge as well as by direct effect on follicular rupture Its action on endometrium can interfere with implantation It may have an advantage, if the woman misses to take the drug within 3 days Adverse effects:- Headache, nausea, vomiting, abdominal pain and menstrual delay

Menstrual Cycle (FOL):

Menstrual Cycle (FOL) F ollicular (Proliferative) O vulatory S ecretary (Luteal) Menstruation

ENDOCRINE CONTROL OF THE Menstruation:

ENDOCRINE CONTROL OF THE Menstruation The cyclic changes in the female reproductive tract are initiated and regulated by the hypothalamic-pituitary-ovarian (HPO) axis Although folliculogenesis occurs independently of hormonal stimulation up until the formation of early tertiary follicles, the gonadotrophins luteinising hormone (LH) and follicle stimulating hormone (FSH) are essential for the completion of follicular maturation and development of mature preovulatory (Graafian) follicles. Pituitary gonadotrophin secretion drives follicular maturation and oestrogen secretion Ovulation is triggered by an oestrogen-mediated preovulatory LH surge The increase in oestrogen observed during prooestrus initiates several characteristic morphological changes in the uterus and vagina This positive oestrogenic modulation of hypothalamic-pituitary function results in a preovulatory LHRH surge and corresponding surge in LH. The LH surge, which closely follows the oestrogen peak triggers ovulation

ENDOCRINE CONTROL OF THE Menstruation:

ENDOCRINE CONTROL OF THE Menstruation Pituitary gonadotrophin secretion drives follicular maturation and oestrogen secretion Ovulation is triggered by an oestrogen-mediated preovulatory LH surge The increase in oestrogen observed during prooestrus initiates several characteristic morphological changes in the uterus and vagina This positive oestrogenic modulation of hypothalamic-pituitary function results in a preovulatory LHRH surge and corresponding surge in LH. The LH surge , which closely follows the oestrogen peak triggers ovulation

Structure of Ovary:

Structure of Ovary

History of Oral Contraceptives:

History of Oral Contraceptives The first steroidal oral contraceptive pill (OCP) was approved in the 1960s The first generation OCPs contained mestranol which was then replaced by EE initially in doses as high as 150 mcg per pill, decreased to 100, 80, and 50 μg then 30 and 20μg Most progestins used in OCPs of the first and second generation were chemically related to testosterone (19-nortestosterone derivatives; estrane and gonane groups). These progestins were responsible for undesirable androgenic side effects

What are the ways for contraception?:

What are the ways for contraception?

Which one to choose?:

Which one to choose?

Types of Contraception (Cafeteria Approach):

Types of Contraception (Cafeteria Approach) Natural (Fertility awareness methods) Sterilization Male- Vasectomy Female- Tubectomy Calendar Ovulation Symptothermal Hormonal monitoring Barrier Methods Male condom Female condom Diaphragm Cervical cap Sponges and spermicides Combined hormonal contraceptives Combined hormonal patch Combined hormonal rings Long acting reversible contraception ( LARC ) Long acting nonhormonal LARC Copper IUD Hormonal LARC Progestin injections (DMPA and NET-EN) Implants Biodegradable Nonbiodegradable

Failure rates of various contraceptive methods:

Failure rates of various contraceptive methods Vasectomy – 0.1 to 0.15 Tubal ligation- 0.5 to 1 IUCD- 0.6 to o.8 Oral Pills- 0.3 to 8 Condom – 2 to 15 Coitus interruptus- 4 to 20

Calendar method:

Calendar method Cycle length is recorded for minimum of 6 cycles Likely fertile days are then calculated allowing for the survival of sperm and ova First fertile day: Shortest cycle – 20 Last fertile day: Longest cycle – 10 Example: If cycles of 26-32 days then Period of abstinence should be practiced from day 6 to 22

8th Session (Hormonal contraception) :

8th Session (Hormonal contraception) Oral Combined Phased Progesterone only Ormeloxifene ( Centchroman , SERMs) Emergency Injectable Mechanism of action Special points Adverse effects Contraindications Interactions Benefits other than contraception

HORMONAL CONTRACEPTIVES :

HORMONAL CONTRACEPTIVES Reversible suppression of fertility The efficacy, convenience, low cost and overall safety of oral contraceptives (OCs)

HORMONAL CONTRACEPTIVES:

HORMONAL CONTRACEPTIVES Combined pill Contains an estrogen and a progestin in fixed dose for all the days (monophasic) First generation with high quantity of Estrogens and progestins Second generation Reduced amount of estrogen and progestin in the ‘’ OC pills Third generation containing newer progestins like desogestrel with improved profile

HORMONAL CONTRACEPTIVES:

HORMONAL CONTRACEPTIVES Combined pill Threshold quantity of Ethinylestradiol 30 μg / 20µg daily The progestin is a 19-nortestosterone (potent anti-ovulatory action) Quantity of progestin Levonorgestrel 60 μg , Desogestrel 60 μg , Norgestimate 200 μg , Gestodene 40 μg Amount in the pill is 2–3 times higher to attain 100% certainty Inhibition of ovulation Both estrogens and progestin Progestin to Ensure bleeding at the end of a cycle Block the risk of developing endometrial carcinoma by estrogen

HORMONAL CONTRACEPTIVES :

HORMONAL CONTRACEPTIVES Combined pill One tablet is taken daily for 21 days Starting on the 5th day of menstruation The next course is started after a gap of 7 days (IRON) in which bleeding occurs This is the most popular and most efficacious method

HORMONAL CONTRACEPTIVES :

HORMONAL CONTRACEPTIVES Phased pill Phasic regimens reduced steroid dose without compromising efficacy Mimicking the normal hormonal pattern in a menstrual cycle The estrogen dose is kept constant (or varied slightly between 30–40 μg ) Progestin is low first then higher in the second and third phases Phasic pills are particularly recommended for Women over 35 years When other risk factors are present

HORMONAL CONTRACEPTIVES :

HORMONAL CONTRACEPTIVES Progestin-only pill ( Minipill ) No estrogen (responsible for most SE) Taken daily continuously without any gap Less popular

Oral contraceptive Preparations:

Oral contraceptive Preparations Combined Pills (Progesterone 100 to 500 ug , Estrogen 20 to 50 ug ) Norgestrel + Ethinylestrodiol (Mala D 300 ug and 30 ug ) Levonorgestrel + Ethinylestradiol Desogestrel + Ethinylestradiol Phased Pills (Progesterone 50 – 75 – 125 ug , Estrogen 30 to 40ug) Levonorgestrel + Ethinylestradiol Norethindrone + Ethinylestradiol Postcoital Pills (Progesterone 250 to 1500 ug ) Levonorgestrel + Ethinylestradiol Levonorgestrel Mini Pills (Progesterone 75 to 350 ug ) Norethindrone Norgestrel

Emergency (Postcoital) pill :

Emergency (Postcoital) pill ‘ Yuzpe method’ Developed by Canadian Professor of Obstetrics and Gynaecology  A. Albert Yuzpe   Woman uses everyday birth control pills as  Emergency Contraception   Use levonorgestrel 500 ug + ethinylestradiol 100 ug , two doses at 12 hour interval Within 72 hours of exposure (Less used now)   Mala - D  and  Mala - N  containing 30µg ethinylestradiol require 4 tablets to be given twice at an interval of 12 hours Levonorgestrel 0.75 mg two doses 12 hours apart, or 1.5 mg single dose taken as soon as possible, but before 72 hours Ulipristal ( SPRM) Ulipristal 30 mg single dose as soon as possible, but within 120 hours of intercourse Mifepristone 600 mg single dose taken within 72 hours of intercourse

Injectable Hormonal Contraceptives (LARC):

Injectable Hormonal Contraceptives (LARC) • Injectable Given i.m. as oily solution (during first 5 days of cycle, once in 2 to 3 months) Highly effective Return of fertility may take 6–30 months after discontinuation Rarely permanent sterility may occur Risk of menopause-like symptoms (hot flushes, vaginal dryness, reduced libido) Risk of complete disruption of menstrual bleeding pattern or total amenorrhoea (DMPA) Only the long-acting progestin only injections are in use Two compounds Depot medroxyprogesterone acetate (DMPA) 150 mg at 3-month intervals (more irreversibility) Norethindrone (Norethisterone) enanthate (NEE) 200 mg at 2-month intervals (more failure rate)

Hormonal Contraceptive Implants :

Hormonal Contraceptive Implants Implanted under the skin Steroid is released slowly over a period of 1–5 years Two types Biodegradable polymeric matrices—do not need to be removed on expiry Non-biodegradable rubber membranes—have to be removed on expiry NORPLANT: A set of 6 capsules each containing 36 mg levonorgestrel (total 216 mg) for subcutaneous implantation, works for up to 5 years PROGESTASERT (P rogesterone impregnated intrauterine insert), contains 52 mg of levonorgestrel which primarily acts locally on endometrium, effective for 5 years

Mechanism of action of hormonal contraceptives:

Mechanism of action of hormonal contraceptives Inhibition of Gn release by reinforcement of normal feedback inhibition Progestin Reduces frequency of LH secretory pulses (PILL) Direct actions on the genital tract (Thick cervical mucus, hostile to sperm) Endometrium is out of phase (hyperproliferative or hypersecretory or atrophic) Modified Uterine and tubal contractions to disfavour fertilization Estrogen Primarily reduces FSH secretion

Mechanism of action of hormonal contraceptives:

Mechanism of action of hormonal contraceptives Both Progesterone and Estrogen synergise to inhibit midcycle LH surge Combined pills inhibit both FSH and LH and abolish mid-cycle surge to inhibit ovulation Minipill and progestin only injectable attenuate LH surge

Mechanism of action of hormonal contraceptives:

Mechanism of action of hormonal contraceptives Postcoital pill When taken before ovulation dampen LH surge and inhibit ovulation Blastocyst may fail to implant ( endometrium not suitable for nidation ) Uterine and tubal contractions modified to disfavour fertilization May dislodge a just implanted blastocyst.

Important Points related to mechanism of action of hormonal contraceptive:

Important Points related to mechanism of action of hormonal contraceptive Injectable Progestin Inhibit LH, (less of FSH), produce hostile cervical mucus, and endometrium gets atrophied, Most effective Combined pills Inhibit both LH and FSH, Also produce hostile cervical secretions, Endometrium is hyper-secretory, More effective Progesterone only pills Inhibit LH only, produce hostile cervical mucus, Endometrium is out of phase Less effective Postcoital pills Inhibit LH and make endometrium unfavourable Least effective Efficacy

Important Points related to mechanism of action of hormonal contraceptive:

If pregnancy occurs during use of hormonal contraceptives Should be terminated by suction-aspiration High risk of malformations, genital carcinoma in female High risk of undescended testes in male Ethinylestradiol Quantity in oral contraceptive pills For most women 30 μg Obese may require 50 μg Very thin, above 40 yrs , with cardiovascular risk only 20 μg Important Points related to mechanism of action of hormonal contraceptive

Important Points related to mechanism of action of hormonal contraceptive:

If breakthrough bleeding occurs Switch over to a pill containing higher estrogen dose In women with contraindications for estrogen Progestin only contraceptive may be used Important Points related to mechanism of action of hormonal contraceptive

Important Points related to mechanism of action of hormonal contraceptive:

ADVERSE EFFECTS Dose dependent, Mostly minor Nonserious side effects Frequent, especially in the first 1–3 cycles, Disappear gradually Important Points related to mechanism of action of hormonal contraceptive Nausea: similar to morning sickness Mild Headache Migraine worsened Breakthrough bleeding or spotting (progestin only) No bleeding at all Prolonged amenorrhoea Cycle disruption Breast discomfort Weight gain Acne Increased body hair (older 19-nortestosterone progestins ) Chloasma : Pruritus vulvae Carbohydrate intolerance Mood swings Abdominal distention (progesterone only)

Important Points related to mechanism of action of hormonal contraceptive:

Serious complications Leg vein thrombosis and pulmonary embolism : Due to estrogen component The older preparations increased the incidence of venous thromboembolism Significant risk in women >35 years of age, diabetics, hypertensives and smokers Coronary and cerebral thrombosis resulting in myocardial infarction or stroke Both estrogen and progestin have been blamed for the arterial phenomena. Increase in blood clotting factors Decreased antithrombin III Decreased plasminogen activator in endothelium Increased platelet aggregation. Rise in BP : If the BP rises, best is to stop Ocs Both the estrogen and progestin components Important Points related to mechanism of action of hormonal contraceptive

Important Points related to mechanism of action of hormonal contraceptive:

Genital carcinoma: Vaginal, cervical, and breast cancers Risk is increased in predisposed individuals Hastening of growth of already existing hormone dependent tumour Minor increase in breast cancer incidence Note:- A protective effect against endometrial carcinoma by progestin component Prolonged suppression of gonadotropin lead to lower ovarian malignancy Benign hepatomas : may turn malignant Gallstones: Estrogens increase biliary cholesterol excretion Important Points related to mechanism of action of hormonal contraceptive

Types of Bleeding:

Types of Bleeding Menstrual bleeding- Normal physiological bleeding due to shedding of endometrium ( Weeping of Uterus ) Withdrawal bleeding- A withdrawal bleed can also occur after a course of progesterone therapy, Sudden low progesterone Spotting- Light vaginal bleeding or brown discharge that occurs between menstrual periods Breakthrough bleeding- Breakthrough bleeding refers to vaginal bleeding or spotting that occurs between menstrual periods or while pregnant (attributed to insufficient  estrogens , hormonal contraception, IUDs, infections, growth etc )

Important Points related to hormonal contraceptive:

Contraindications Exercise:- Please correlate with pharmacological properties of hormonal contraceptives Important Points related to hormonal contraceptive Relative contraindications Diabetes mellitus Obesity Smoking Undiagnosed vaginal bleeding Uterine leiomyoma (progestin pills can be) Mentally ill Age above 35 years Mild hypertension Migraine Gallbladder disease Absolute contraindications Thromboembolic, coronary and cerebrovascular disease or a history of it Moderate-to-severe hypertension; Hyperlipidaemia Active liver disease, hepatoma H/o jaundice during past pregnancy Malignancy of genitals/ breast Prophyria Impending major surgery—(to avoid excess risk of postoperative thromboembolism)

Important Points related to hormonal contraceptive:

Interactions Contraceptive failure may occur with following drugs Enzyme inducers: Phenytoin, phenobarbitone, primidone, carbamazepine, rifampin , ritonavir Suppression of intestinal microflora: Tetracyclines , ampicillin , etc. Deconjugation of estrogens excreted in bile fails to occur → their enterohepatic circulation is interrupted → blood levels fall Note:- Switch over to a preparation containing 50 μg of ethinylestradiol or to use alternative method of contraception Important Points related to hormonal contraceptive

Important Points related to hormonal contraceptive:

Other health benefits (other beneficial effects as a bonus) Important Points related to hormonal contraceptive Lower risk of developing endometrial and ovarian carcinoma Lower risk of developing colorectal cancer Reduced menstrual blood loss and associated anaemia Regularization of menstrual cycles Reduction in premenstrual tension Reduced dysmenorrhoea Reduced menorrhagia Improvement in Endometriosis Improvement in pelvic inflammatory disease Reduced incidence and symptomatic relief of fibrocystic breast disease Reduced incidence and symptomatic relief of ovarian cysts Menstrual flare of rheumatoid arthritis Vasomotor symptoms of perimenopause Acne Hirsutism Polycystic ovary syndrome

Ormeloxifene (Centchroman) :

Ormeloxifene ( Centchroman ) Nonsteroidal SERM developed at CDRI India as an oral contraceptive Predominant estrogen antagonistic action in uterus and breast with little action on vaginal epithelium and cervical mucus Endometrial proliferation is suppressed by down regulation of endometrial ER. Contraceptive action is probably due to utero- embyonic asynchrony Failure of implantation Pituitary, ovarian and other endocrine functions remain practically unaffected Menstrual cycle is not disrupted Also approved for use in dysfunctional uterine bleeding

Ormeloxifene (Centchroman) :

Ormeloxifene ( Centchroman ) The plasma t½ of ormeloxifene is long (~1 week). It prevents conception as long as taken with return of fertility few months after stoppage Side effects are nausea, headache, fluid retention, weight gain, rise in BP and prolongation of menstrual cycles Dose : For contraception 30 mg twice a week for 12 weeks followed by once a week. For dysfunctional uterine bleeding 60 mg twice a week for 12 weeks, then once a week for 12 weeks

Why male are less bothered about contraception?:

Why male are less bothered about contraception? Male don’t become pregnant

MALE CONTRACEPTIVE :

MALE CONTRACEPTIVE To inhibit spermatogenesis, No satisfactory/ acceptable solution Reasons are Complete suppression of spermatogenesis is relatively difficult without affecting other tissues Millions of spermatozoa are released at each ejaculation vs a single ovum per month in women Spermatogenesis takes 64 days Gonadotropin suppression inhibits testosterone secretion as well, resulting in loss of libido and impotence Drugs used for male contraception Superactive Gn RH analogues i nhibit Gn release, inhibit testosterone secretion as well Androgens inhibit Gns but have poor efficacy. Even combination with progestin is not reliable Antiandrogens Depress spermatogenesis, but raise Gns ; cause unacceptable loss of libido Estrogens and progestins Act by suppressing Gns , cause unacceptable feminization Cytotoxic drugs Cadmium, nitrofurans and indoles suppress spermatogenesis, but are toxic Gossypol a nonsteroidal compound, obtained from cotton seed ; effective orally—causes suppression of spermatogenesis and sperm motility, involves direct toxicity on seminiferous epithelium. Most important adverse effect is hypokalaemia (due to renal loss of K+) with its attendant muscular weakness

Postpartum and contraception :

Postpartum and contraception The postpartum period is an important time to evaluate the safe use of contraception Ovulation can occur as early as 25 days after delivery among non-breastfeeding women Breastfeeding must constitute 85%–100% of the infant’s feeds in order to rely on breastfeeding to suppress ovulation

How to be reasonably certain that a woman is not pregnant:

How to be reasonably certain that a woman is not pregnant If she has no symptoms or signs of pregnancy and meets any one of the following criteria It is < 7 days after the start of normal menses She has not had sexual intercourse since the start of last normal menses It is < 7 days after spontaneous or induced abortion It is within 4 weeks postpartum She is fully breastfeeding (Exclusively breast feeding), amenorrhoeic and < 6 months postpartum

Screening when providing contraceptive services:

Screening when providing contraceptive services History Reproductive life plan Medical history Current pregnancy status Sexual health assessment Tobacco use Age Physical Examination Height, Weight, BMI Blood pressure Pelvic examination Laboratory testing Pregnancy test Lipid profile, Blood sugar, INR

Relax and Revise:

Relax and Revise There are many methods for contraception The best choice depends on individual preferences and health Combined oral pills are one of the most accepted and trusted methods Minipills contain only progesterone Injectable long duration contraceptives are progesterone only Estrogen and progesterone both reduce LH surge and ovulation Progesterone makes cervix not suitable for survival of sperms Emergency contraception should be taken within 72 hours

Which of the following component is most commonly used estrogen in combined pills?:

Which of the following component is most commonly used estrogen in combined pills? Ethinylestradiol Estradiol Estrone Tibolone Ans :- A

In phased pills concentration of which component changes? :

In phased pills concentration of which component changes? Ethinylestradiol Levonorgestrel Danazol Dienestrol Ans :- B

Depot medroxyprogesterone acetate (DMPA) is injected at regular intervals of :

Depot medroxyprogesterone acetate (DMPA) is injected at regular intervals of 3 days 3 months 3 years Only once Ans :- B

Contraceptive discovered at CDRI Lucknow is:

Contraceptive discovered at CDRI Lucknow is Mala D Mala N Ormeloxifene Mini-pill Ans :- C

Gossypol can be of some use in:

Gossypol can be of some use in Male contraception Postcoital contraception Postpartum contraception Intrauterine contraception Ans :- A

To Summarize todays learning activity:

To Summarize todays learning activity Hormones Endocrine glands Names GnRH Super active GnRH analogues ( Nafarelin , Goserelin , Triptorelin, Leuprolide, GnRH antagonist (Ganirelix, Cetrorelix ) Androgens Natural (Testosterone, Dihydrotestosterone, Androsterone) Synthetic (Methyltestosterone, Fluoxymesterone, Mesterolone). Anabolic steroids (Methandienone, Oxymetholone, Nandrolone, Stanozolol)

To Summarize todays learning activity:

To Summarize todays learning activity Antiandrogens (Cyproterone acetate, Flutamide, Bicalutamide) 5 alpha reductase inhibitors (Finasteride, Dutasteride) Pharmacotherapy of erectile dysfunction, Phosphodiesterase 5 inhibitors (Tadalafil, Vardenafil, Sildenafil), PIPE, Alprostadil Estrogens Natural (Estradiol, Estrone, Estriol) Synthetic Ethinylestradiol Mestranol Tibolone (All PET) Diethylstilboestrol Hexestrol Dienestrol

To Summarize todays learning activity:

To Summarize todays learning activity Antioestrogen (Clomiphene citrate) SERDs (Fulvestrant) SERMs (Tamoxifen, Toremifene, Raloxifene) Aromatase inhibitors (Letrozole, Anastrozole, Exemestane) Progestins Natural (Progesterone) Synthetic (Progesterone derivatives [Medroxyprogesterone, Megestrol, Dydrogesterone , Hydroxyprogesterone] 19-Nortestosterone derivatives [{Estranes- Norethindrone, Lynestrenol, Allylestrenol }, {Gonanes- Levonorgestrel, Desogestrel , Norgestimate , Gestodene }]

To Summarize todays learning activity:

To Summarize todays learning activity HRT Menstrual cycle Impeded androgen (Danazol) Antiprogestins (Mifepristone, Ulipristal) Hormonal contraceptives Combined pill Phased pill Mini pills Postcoital pill LARC [ Depomedroxy progesterone acetate, Norethindrone enanthate, Ormeloxifene ) Male contraceptives

THANKS :

THANKS dixitkumarrakesh@gmail.com Any Comment or Query?

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