hormones in gynae

1. Dr. PRIYANKA

2. 1926-27: discovery of pituitary hormones
1955: clinical use of urinary hormone assays
1957: extraction of gonadotropins from
human pituitary & urine
1958: Gemzell reported first pregnancy
following use of human pituitary
gonadotropin
1960: Lunenfeld reported first pregnancy
from HMG

3. 1971: isolation of GnRH by Schally & Guillemin
1972: discovery of GnRH antagonists
1978: first IVF baby Louise Brown in UK (Steptoe
& Edwards) in natural cycle
1981: GeorgeannaJones first used HMG for
oocyte retrieval in IVF
1982: first GnRH use for pituitary down-
regulation in IVF
1985: human pituitary extracts abandoned after
reported CJ disease
1991: first clinical use of GnRH antagonist in IVF

5.  Small decapeptide
 Encoded by Ch.8p
 Released from Arcuate nucleus of hypothalamus
 Short half-life of 2-4 min.
 Stimulates FSH & LH release from Pituitary
 Pulsatile & rhythmic release
 Enhanced pulsatility during puberty

6. FOLLICULAR PHASE LUTEAL PHASE
High frequency ( once in 60
mins)
Low amplitude
Low frequency ( once in 90 -
120 mins)
High amplitude

7. Hypothalamus
(ultrashort) GnRH
Pituitary (short)
FSH & LH
(long feedback)
Ovary
Estrogen & progesterone

8.  Gonadotropins – glycoproteins with identical
alpha subunit, specific beta subunit
 Types – Follicle Stimulating Hormone (FSH)
Luteinising Hormone(LH)
 GnRH analogues – agonist
antagonist

9. FSH LH
FSH receptor (ch 2q) LH receptor (ch 2p21)
GnRH GnRH, High estrogen
Estrogen, Inhibin Moderate level of estrogen
Two peaks during menstrual cycle
FOLLICULAR PHASE : 6th day
PREOVULATORY PHASE : 12th
day
Present in low level throughout
menstrual cycle
PEAK LEVEL : 24 hrs – 36 hrs
before ovulation

10. FSH( mIU/ml) LH(mIU/ml)
 Women:
-follicular 3-12 1.8-13.4
-periovulatory 8-22 15.6-78.9
-luteal 0.7-
19.4
-post menopause 12-30 >50
 Men : 1-14 1.5-9.2

11.  LH & FSH receptors –
GPCR
 Gn couple GS alpha
↑ AC & cAMP
 High concentration of
agonist ↑ PKC, ↑ Ca
signalling

12. GRANULOSA CELL
THECA CELL

13. LH ( FUNCTION) FSH (FUNCTION)
FEMALE :
Recruitment and growth
of follicles
Acts on Granulosa cells :
Number, LH receptors,
aromatase activity
FEMALE :
Triggers ovulation
Theca cells : androgen
production
Corpus luteum : progesterone
MALE
Sertoli cells -
spermatogenesis
MALE
Leydig cell : Sex steroids
INHIBIN B INHIBIN A

16. Generic name Trade
name
Source FSH/amp LH/amp Route
Menotropin Humegon,
Pergonal
(Rs.600)
Urinary HMG 75 IU 75 IU IM
Urofollitropin Metrodin
(Rs.850)
Purified uFSH 75 IU 1 IU IM
Purified
urofollitropin
Fertinex HP-uFSH 75 IU <0.1 IU SC
Follitropin
alpha
Follitropin beta
Gonal-f
(Rs.1200)
Follistim
recFSH 75 IU NONE SC

17. Diagnostic
Therapeutic
Diagnostic :
 Prediction of ovulation
 Reproductive disorders
-Hypogonadotropic hypogonadism (low levels)
-Primary gonadal failure (high levels)
-Amenorrhoea & delayed puberty
• Day 3 FSH >15 IU/ml –reduced fertility & success in IVF
(96% specificity along with CCCT)
Fertil Steril
2000:73

18. Therapeutic : female infertility
male infertility
cryptorchidism
1. Female infertility
- ART
- Hypogonadotropic hypogonadism (Group I)
- PCOS (Group II)
- Infertility despite normal ovulation

19. Gn – used in infertile patient for
 ovulation induction
 superovulation
Ovulation induction- therapeutic restoration
of release of 1 egg/cycle in those who are not
ovulating at all or ovulate irregularly
Superovulation- in those not concieving
despite regular ovulation goal being release
of >1 egg/cycle , thereby ↑ing probability of
conception

20. OVI Superovulation
Along with
-Clomiphene citrate -Gn+ GnRHa
-Aromatase inhibitors -Gn+ GnRH-nt
-Insulin sensitizers
-LOD
(Group I ,II disorders ( ART-IVFET,ICSI
PCOS ) unexplained, IUI)

21. 2.Male infertility
Men with hypogonadotropic hypogonadism when treated with
HCG/FSH show ↑ in sperm count, motility, morphology &
testicular volume
HCG (1000-5000 IU) thrice weekly until adequate plasma
concentration of testosterone is detected
If sperms are undetected after 6 months, concomittant therapy
with HMG (75-150 IU) twice/ thrice weekly or FSH (50-150 IU) IM
thrice weekly ensues
Average takes 6 to 9 months for sperms to appear in ejaculate,
therapy up to 1-2 years may be needed
Am Urol Assoc 2007 Update
3.Cryptorchidism without anatomical blockade
-CG 3000 U/m BSA IM every other day x 6 doses
Endocrinol Metab Clin N Am36 (2007)

22. Significant space occupying lesions in brain or
pituitary.
Undiagnosed breast or genital pathology.
Ovarian failure.
Hypersensitivity to gonadotropins.
Uncontrolled thyroid & adrenal dysfunction
Ovarian cysts /enlargement not due to PCOS
Pregnancy
Sex-hormone dependent tumor of reproductive
tract

23.  Stimulate release of LH & FSH
 Continuous administration produces
antireproductive effect due to desensitization of
GnRH receptors on pituitary gonadotropes
 Initial flare-up response for 1-3 weeks
 Effect on LH secretion is more pronounced than
FSH due to shorter half life of LH
 Route : IM ,IV ,SC, Nasal

24. Name administration dose frequency
Leuprolide * (Lupride)
Rs.4000
sc 500 mg daily
im 3.75 mg/11.25mg Monthly/ 3 monthly
Goserelin* (Zoladex)
Rs.6000
sc 3.6 mg monthly
Buserelin in 300 ug daily
sc 200 ug daily
Naferelin in 200 ug daily
Triptorelin*
(Decapeptyl) Rs.4000
im 3.75 mg monthly

25.  Short term(<6 months)
 Endometriosis
 uterine leiomyoma
 ovulation induction
 diagnosis of ovarian disorders
 Long term(>6 months)
 precocious puberty
 cancer (prostate & breast)
 endometriosis(pain)
 hyperandrogenism

26.  Indications
 OI with TI / IUI
 Superovulation in ART
 Patients at risk for OHSS
 Prevent premature ovulation
 Advantage:
 When administered with Gn, it reduces cycle
cancellation due to premature ovulation
 Less intensive monitoring is required
 Helps in programming oocyte retrieval
 Reduces complication like OHSS

27.  Most c/n condition for use of gonadorelin analogue
 Goserelin & leuprorelin commonly used
 Indications –
- Pain (dysmenorrhoea,dyspareunia)
- Infertility
 Remission rather than cure
 Efficacy GnRH/danazol/progestins similar
 Different cost & safety profile
Hum Reprod Update 2006Mar12(2)179-80

28.  Therapy-
 Dosage: depot inj. 3.75 mg once a month
depot inj. 11.25 mg 3 monthly
 Route: IM or SC
• Preoperatively: 3 months
• Postoperatively : 1-2 months (infertility)
6 months (pain)
 When to start GnRH after conservative surgery in
endometriosis:
• Midluteal phase as agonist flare effect is least at this stage
of cycle, rapid achievement of pituitary suppression
Obstet Gynecol Clin N Am 2003;30

29. Pain relief- 86-92% after 6 months of use & effect lasts for
12 months
Obstet Gynecol Clin N Am 2003
No significant improvement in fertility outcome when given
postoperative
RCOG 2005
ESHRE 2006
GnRH agonist given for 3 months in endometriosis before IVF
improves clinical pregnancy rate by 15-20%
Fertil Steril 2002;78:699-704
Demerits
 recurrence (30-70%) ,mean length of time ~6-18 mths
 osteoporosis (1%/m after 6 months)
 high cost

30. First used in 1983
Basis: medical oophorectomy/ pseudomenopause
Filicori et.al( Am J Obstet Gynecol 1983)
Preoperatively- myomectomy / hysterectomy
uterine volume (0-96%)& size by 30-50%
vascularity→ i.o.blood loss
adhesion
hospital stay & morbidity
 Allow for vaginal route of surgery / transverse incision
 Reduction in size correlates with E2 levels (<50 pg/ml)
& body weight
Obstet Gynecol Clin N Am 2006

31.  Severe anemia-↓ menorrhagia, improve Hb
 Medical Mn- perimenopausal women
-comorbid illness
-infertility (submucosal/cornual myoma)
BJOG 2002 Oct(109)10:1097-108
Cochrane Database Sys Rev;2001
 Duration : 3 months preoperative
6 months as medical therapy
64% remain asymptomatic after 3-6 months
Obstet Gynecol Clin N Am 2006

32.  Disadvantage:
 Regrowth of myoma after 3-6 months of
discontinuation of therapy
 Degenerative changes
 Loss of cleavage plane
 Small myoma may be missed during surgery
 High cost
 Side effects: hot flashes , vaginal dryness,
hypoestrogenism, loss of BMD
Fertil Steril 2007,88(2)

33. central(true)-premature
activation of hypothalamus
Types
pseudo(gonadal)-↑ sex steroid
Chronic GnRH agonist in idiopathic central
↓ Gn to prepubertal levels
↓ estrogen & testosterone conc.
Regression of sec. sex ↑ in predicted
characters adult height

34. FDA approval in prostatic carcinoma
Alternative to Sx for pt refusing orchiectomy or
estrogen
86 % cases treated showed no progression
Efficacy similar to DES with latter having ↑ side
effects
MOA- ≠ androgen production (medical castration)
Neoadjuvant androgen deprivation- GnRHa eradicates
maignant cells outside capsule
ClinTher2005;Mar27 (3)

35. Breast carcinoma
Goserelin licensed for ER-positive breast Ca in
premenopausal women
Endocrin Rev 1986;7:89
Combination with tamoxifen improves outcome
Gynec Obstet Fertil 2005Nov33(11)
No significant effect in postmenopausal
? Role with aromatase inhibitors
Cancer 2006Feb 1(183)

36.  Premenstrual syndrome – abolish hormone
fluctuation
 Porphyria -? Role
 Contraception- low dose agonist + progesterone in
females
low dose agonist + testosterone in men
? Effectiveness, cost & s/e has limited this use

37.  Hypoestrogenism –hot flushes (72%), vaginal dryness(28%) ,↓
libido, breast changes, acne
 Osteoporosis (6-8% loss in BMD) after 6 months , not
completely reversible on discontinuation
FertilSteril 2000;74:964-68
 Sleep disturbances(60-90%)
 Mood swings , depression(20-30%)
 Irregular vaginal bleeding(20-30%)
 Headache (20-30%)
 Adverse lipid profile (↑ LDL, ↓ HDL)
ObstetGynecol Clin N Am2003

38.  Goal : to prevent vasomotor symptoms & bone
loss due to hypoestrogenic state induced by
GnRH agonist when administered longer than 6
months & in perimenopausal women
 Regimens:
1.Progestins- norethisterone(1.2 mg)
- norethindrone acetate(5 mg)
2.E+P- CEE(.625 mg)+ MPA(2.5 mg)
JAMA 2002;287:2668-76
3.Tibolone (2.5 mg)
Fertil Steril 2000;74:534-39

39.  Structure- substitution of 4-6 AA for non natural
D-aminoacids in agonist
Endocrinol Metab.1992;3:259-63
 MOA- competitive inhibitors
- bind to GnRH receptor with high affinity
leading to inhibition of receptor dimerization &
subsequent gonadotropin secretion
Clin Obstet Gynecol 2003;46:254-64

40. GnRH antagonist GnRH agonist

41.  First generation – release of histamine from skin
at injection site (DArg class )
Endocr Rev 1986;44-46
 Second generation- no histamine release
Name Availability
Abarelix NA
Antarelix NA
Cetrorelix* (cetrotide) Available in India (Rs.920)
Ganerelix NA
Iturelix NA
FE200486 NA

42.  Ovarian hyperstimulation
 Endometriosis
 Fibroid
 Central precocious pubety

43.  Inhibition of LH & FSH secretion
 No desensitisation period → no flare-up
 Immediate & fast response
 Postpone LH surge if administered at the end of
follicular phase - prevent premature ovulation
 Onset of action: 2-4 hrs
 Programming of IUI (avoiding weekends)
Fertil Steril2006,vol.85
Hum Reprod Update 2002;8:279-90

44. GnRH agonist GnRH antagonist
Cancellation rate 56.3% 32%
Duration of Gn (days) 10± 2 8.6±2
OHSS 27.6% 11%
ET rate 76% 96%
Pregnancy rate 52% per ET 31% per ET
Hum Reprod 2007Nov (11);22
• GnRH-nt have significantly lower pregnancy rate than GnRH agonist
• GnRH-antagonists allow shorter stimulation schemes , reduce direct IVF
cost & improve patient satisfaction
• Reduce IVF risk & indirect cost by preventing OHSS
• Main challenge is to improve pregnancy rate
Olivennes et al;Clin Obtet Gynecol2006;49

45. Cetrorelix 3 mg once wkly X 8 wks
Symptom free period during treatment
Estradiol ↓ to 50pg/ml
No flare-up response
Lesions declined from stage III to II after 8 wks
Felberbaum et al Reprod Biomed 2002;512-16
No estrogen deficiency symptoms
 Further studies needed for long-term application
of GnRH-nt in endometriosis
Clin Obstet Gynecol 2003;46

46.  Preoperative alternative to GnRH agonist
 Significant reduction of treatment duration , mean duration
being 19 days
 Ganirelix 2mg/d
 Cetrorelix 3mg every fourth day for 2-4 wks
 Depot cetrurelix 60mg on D2 followed by 60/30mg on
D21/28
 Significant ↓ in fibroid size & vascularity
 Reduction in myoma size (43% on USG, 29% on MRI
 Decrease in uterine volume(47% on USG, 25%on MRI
Fleiman et al, BJOG
2005;112(5)
Reprod Biomed 2002;5:68-72

47. 1.Central precocious puberty- rapidly suppress
Gn & sex-steroid levels
 Effect is reversible & resumption of normal
menses & fertility is proved after cessation of
therapy
 Efficacy equivalent to GnRH agonist
Clin Obstet Gynecol2003;46:260
2.Male contraception – along with androgen
supplement Hum Reprod.2001;16:2570-2577

48. 3. Breast cancer – intermittent long acting
forms provide compliance & comfort
? efficiency & safety
4. Preoperative preparation for hysteroscopy
5.Before mammogram to eventually reduce
breast density
Clin Obstet Gynecol 2003;46:254-64

49.  Gonadotropin use for infertility has significantly
improved the pregnancy outcome along with GnRH
agonist (long protocol) in IVF
 Low dose step-up protocol of Gn has been proved
to be most cost effective
 GnRH agonists have revolutionized the success of
IVF
 GnRH agonists have definite role in endometriosis,
fibroid & precocious puberty
 Further studies are needed on the use of GnRH
antagonist against agonists

51. NATURAL
ESTROGEN
SYNTHETIC
STEROIDAL
ESTROGEN
SYNTHETIC NON
STEROIDAL
ESTROGEN
CONJUGATED
ESTROGEN
Estradiol
Estrone
Estriol
Ethinyl estradiol
Mestranol (prodrug)
Quinesterol
Tibolone
Stilbestrol
Dienestrol
Chlorotrianisene
Mixture of sod.
Estrone sulphate &
sod. Equiline sulphate

63.  HRT for post menopausal symptoms
 Osteoporosis
 Vasomotor symptoms
 CVD
 Urogenital atrophy
 Neuroprotective and CNS effects
 ERT in Primary ovarian failure
 Dysfunctional uterine bleeding
 Dysmenorrhoea
 Acne and Hirsutism
 Prostate cancer, migraine and Colon cancer

64.  Conjugated equine estrogens (0.625mg/day)
 Estradiol transdermal patch
 Estrogen ( cyclic) + progesterone – to control endometrial
proliferation
 Bisphosphonates- Alendronate as alternative
 Vit D, Calcitonin & PTH supplements
 Raloxifene – DOC
 Endometrial biopsies- every year

65. VASOMOTOR SYMPTOMS –
 Hot flushes are most common in postmenopausal
 Release of LH due estrogen absence
 Short term treatment with conjugated equine estrogen
 Medroxy progesterone is effective

97. CLASSIFICATION BY
STRUCTURE
FIRST SECOND THIRD
ESTRANES Ethynodiol diacetate
Norethindrone
Norethindrone
acetate
GONANES Norgestrel (Ovrette) Levonorgestrel
(Norplant;
With ethinyl estradiol:
Alesse, Nordette)
Desogestrel
(with ethinyl estradiol
: Desogen)
Gestodene
Norgestimate
PREGNANES Medroxy
progesterone acetate
(Provera)

102. OBSTETRICS
 Threatened Abortion
 Recurrent Abortion
 PTL
GYNAECOLOGY
DIAGNOSTIC – PCT
THERAPEUTIC
 Disorders of Menstruation
and Ovulation
 Amenorrhoea
 DUB
 Endometriosis
 Spasmodic
dysmenorrhoea
 PMS
 LPD
 LPS IN ART
 BREAST CONDITIONS
 HRT
 CONTRACEPTION
 CANCER

129. OTHER USES
• Endometriosis
• Leiomyoma
• Ovarian
cancer
• Meningioma
• Breast cancer
• Psychotic
depression

131.  Onapristone
 Epostane

132.  Asoprisnil
 Under trial for use in endometriosis,
leiomyoma and breast cancer