Hormones In Gynaecological Practice Flashcards
Hormones
Factors
Analog
Agonists
Antagonists
■Hormones:
Hormone is a substance that is produced in a special tissue and released into the bloodstream. Hormones travel to distant cells to have its desired effects.
■Factors: Factors are substances that modulate cell function and proliferation by acting upon the cell membrane receptors. They act locally (unlike the hormones) by autocrine and paracrine mechanism.
■ Analogs: An analog is a synthetic substance with a structure mostly similar to a natural one but different from it in certain component. It may have agonist and/or antagonist function at the cellular level. Gonadotropin-releasing hormone (GnRH) analog acts as an agonist (upregulation) initially but on chronic therapy, it antagonizes (downregulation) the pituitary GnRH receptors.
■Agonists: Agonist is a substance that has increased affinity for cell receptors and it stimulates the cellular physiological response.
■Antagonists: An antagonist tends to nullify the action of another substance binding on its receptor without eliciting a biological response. There is a blockage of receptor response. Tamoxifen blocks estrogen receptor whereas mifepristone blocks progesterone receptors. Because of relative lack of receptor specificity, an antagonist for one class of hormone can have an antagonistic effect on another class of hormone.
Antagonists may have adverse effects apart from the intended use.
Cellular Functionmodulated in which three ways
Endocrine, Paracrine, Autocrine?
CELLULAR FUNCTION
A cell function is modulated by any of the three ways:
- Endocrine when a hormone in circulation (blood or lymph) regulates the function of a cell at a distant site.
- Paracrine function is when a regulating substance diffuses from one cell to a contiguous cell (intercellular)! and modulates the cell function. Insulin-like growth factor-II (IGF-II) is produced by the theca cells of ovary. It stimulates granulosa cell proliferation when it diffuses to it.
- Autocrine function is explained when a regulating substance produced by a cell act upon the receptor on the same cell. It modulates the function of the same cell (intracellular). IGF-II is said to have autocrine function when it is produced by and acts on luteinized granulosa cells.
GnRH Diagnostic and Therapeutic uses?
GnRH
It is used for activation of hypothalamo-pituitary-gonadal function (p. 54).
■Diagnostic
■ Therapeutic
■Diagnostic: The GnRH stimulation testi is used to differentiate an amenorrhea of pituitary from hypothalamic in origin (p. 395).
An intravenous (IV) dose of GnRH 50-100 µg is given to stimulate pituitary. The maximal response is observed at 15-30 minutes for luteinizing hormone (LH) and 30-60 minutes for follicle-stimulating hormone (FSH). The absence of response usually denotes pituitary fault. However, the result may not be unequivocal and as such, requires cautious interpretation.
■Therapeutic: The pulsatile nature of hypothalamic GnRH in the control of gonadotropin secretion affords a physiological basis for the activation of pituitary gonadal axis. •
1. Induction of ovulation: It is suitable in cases with idiopathic hypogonadotropic hypogonadism who have failed to respond with clomiphene.
Pulsatile administration of GnRH (2.5-20 µg/pulse) at a constant interval (60-90 minutes) induces ovulation effectively. GnRH therapy results follicular growth and development similar to a normal cycle.
In hypothalamic causes of anovulation, GnRH is most effective.
For IV route, portable minipump is used. For subcutaneous route high dose (20 µg) is needed.
The main advantages of pulsatile administration are lower incidence of hyperstimulation syndrome and multiple pregnancy when compared to human menopausal gonadotropins (hMG).
Other uses through activation of pituitary-gonadal axis:
1. Delayed puberty-to activate the pituitary- gonadal axis (p. 43)
2. Functional hypothalamic amenorrhea to stimulate hypothalamic-pituitary-ovarian (HPO) axis for ovarian follicular development 3. Cryptorchidism
4. Hypogonadotropic hypogonadism (p. 377).
GnRH analogs
GnRH agonists
Mechanism of action
Mode of Adminstration
GnRH Agonist
This is produced when there is substitution of amino acids at 6 and 10 positions (Fig. 7.2, p. 54). This makes GnRH more stable with increased receptor affinity.
Mode of Action
Initially, there is stimulation of anterior pituitary resulting in increased secretion of FSH and LH (upregulation). This is called flare effect. After 1-3 weeks, there is profound suppression of secretion (downregulation) due to loss of pituitary GnRH receptor sensitivity. This leads to a fall in pituitary gonadotropic hormones-LH and FSH, consequently the gonadal secretion (hypogonadotropic hypogonadal state). The net effect is production of medical hypophysectomy.
Mode of Administration
It can be used by intranasal and subcutaneous route and the biodegradable implants last for a month (Table 32.1).
Uses of GnRH agonists?
■ Controlled ovarian stimulation in IVF: Suppression of endogenous pituitary gonadotropin secretion by downregulation with GnRH analogs followed by administration of hMG or FSH allows good quality stimulation with superovulation. The problems of suboptimal response and premature luteinization due to endogenous LH surge are thus avoided. This will allow significantly higher number of oocyte retrieval and significant improvement in pregnancy rate. It is preferable to support the luteal phase with hCG.
Protocol: Two types of protocols are commonly used with probably of equal efficacy (p. 207).
a. Long protocol: The GnRH analogs are given from 21st day of previous cycle to desensitize the pituitary [LH level <5 mIU/ ml. and estradiol (E₂) <30 pg/mL or when ultrasonogram (USG) fails to detect follicle before the hMG or FSH is given. The benefits include less need of cycle monitoring, high pregnancy, and livebirth rates.
b. Short protocol: The hMG or FSH is given soon after administration of GnRH agonists on day 2 and before the pituitary is desensitized. The advantages of short protocol are the economy and convenience, using for a short period of time.
■Induction of ovulation with higher baseline LH in polycystic ovarian syndrome (PCOS): In refractory cases of ovulation induction, especially in patient with polycystic ovaries (PCO), when the endogenous LH level is high, GnRH analogs offer a good success with long protocol regimen. It is used in the in vitro fertilization (IVF) cycles (p. 207).
■ Endometriosis: By producing medical hypophysectomy and thereby, a hypoestrogenic state, it produces atrophy of the ectopic endometrium. GnRH agonists are very effective in relieving the pain and reducing adhesion formation.
■Leiomyoma: By producing hypoestrogenic state, they will produce shrinkage of the tumor by about 60% after 3-6 months treatment. But the size comes back to previous state after the drug is withdrawn. The drug cannot replace surgery. Blood loss during operation is less but surgical dissection may be difficult due to softening of the myoma. GnRH antagonist (depot cetrorelix) preoperative treatment has faster response (14 days) and is equally effective (p. 232).
■Precocious puberty (p. 40): In only constitutional variety, to inhibit the premature activation of hypothalamo-pituitary-gonadal axis, the analogs are safe and highly effective.
Dose: 100 µg intranasally twice daily for 6 months or until the chronological ages are matched (Ch. 5).
■Hirsutism: In the idiopathic group, by suppressing the pituitary-gonadal axis, the excess hair growth can be arrested with the use of GnRH analogs.
Dose: Nafarelin 100 µg per day subcutaneously will decrease the serum level of total and free testosterone and there is clinical improvement of hirsutism.
Dysfunctional uterine bleeding (DUB): During the time, the patient waiting for operation or during the period to improve the anemic state (p. 159).
■ Premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD) (p. 150): It is used for diagnostic as well as therapeutic purpose.
For diagnostic purpose, a depot preparation is administered for 3 months. Leuprorelin acetate, 11.25 mg is given every 3 months for maximum 6 months. Relief of symptoms confirm the diagnosis (p. 150).
Symptoms due to hypoestrogenism is a problem. Add-back therapy may be needed (see below).
■ Advanced breast carcinoma in premenopausal women (Estrogen dependent).
■Contraception: Used for ovulation inhibition and suppression of spermatogenesis (female and male) (Ch. 30).
Used in male: (i) GnRH analogs produce a decline in sperm density, sperm mobility and testosterone level. The marked loss of libido makes it unacceptable. Currently, use of GnRH antagonist along with testosterone (add-back therapy) is found to overcome the problem. (ii) Prostatic cancer (hormone dependent).
Used in female: GnRH analogs act by preventing the pituitary response to endogenous GnRH. Buserelin is given intranasally (Table 32.1). Add-back therapy is effective to prevent the hypoestrogenic symptoms (see below).
Endometrial resection/ablation: Prior to endo- metrial resection, GnRH analogs are used to suppress the endometrial growth (p.1522).
GnRH Antogonists?
Hazards of GnRH Analogs?
GnRH agonists vs GnRH antogonists?
GnRH Antagonist
It is synthesized by modification of amino acids at positions 1, 2, 3, 6 and 10 (Ganirelix, Cetrorelix). Minimum effective dose to prevent premature LH surge is 0.25 mg SC. Elagolix ,an oral GnRH antagonoist, is used for the control pain in endometriosis. The important properties of GnRH agonist and antagonist are given in Table 32.2.
Hazards of GnRH Analogs
Side effects are predominantly due to hypogonadotropic and hypoestrogenic state. The important side effects are hot flashes, vaginal dryness, dyspareunia, headache, and depression (menopause-like symptoms, Ch. 6). Acne, muscle pain, back pain, dry skin are also noted. There is decrease in both, the trabecular (lumbar spine) and cortical (femoral neck) bone mineral density (osteoporosis) when used for more than 6 months. They do not produce significant changes in lipid metabolism. For long-term use, GnRH analogs have been used with low-dose estrogen and progestin (add-back therapy) to minimize the side effects. Add-back therapy consists of low-dose combined estrogen (conjugated estrogen 0.625 mg) and progestin (medroxyprogesterone 2.5 mg) therapy regimens daily. Add-back therapy prevents bone loss and other side effects.
Gonadotropins
Limitations
Indications
Contra-Indications
The use of gonadotropins in clinical use lies on the principle that gonadotropic hormones act on the ovaries to induce ovulation. The gonadotropins, used widely today, are derived from urine obtained from postmenopausal women. Human gonadotropin can also be obtained from extract of cadaveric pituitary glands. Human pituitary gonadotropin (hPG) is predominantly FSH. It is not easily available.
The most commonly used commercial preparation is hMG. One ampoule of hMG (pergonal) contains LH activity of 75 IU and FSH activity of 75 IU. Purified FSH (Metrodin-75 IU/ampoule) is available with minimum LH. Highly purified preparation of human FSH can _ be administered subcutaneously. Recombinant FSH (Gonal F or Recagon) is now available. It is administered by subcutaneous route.
hCG is known to have a biological action like LH surge and is available in ampoules with 1000-5000 IU. It is obtained from urine of pregnant women. Recombinant gonadotropins (FSH, LH, and hCG) are used for ovarian stimulation according to the need of individual woman and to optimize oocyte quality and cycle fecundity.
Limitations
■It is expensive.
■ It should only be used with back-up facilities for monitoring the response by basal body temperature (BBT), cervical mucus study, supplemented by serial serum estradiol estimation, and sonographic measurement of follicular enlargement (Ch. 17). As such, its use is limited only in women with adequate ovarian reserve (p. 444).
Indications
In Anovulatory infertility where other factors (tubal, uterine, male) have been excluded.
■Induction of superovulation in assisted reproduction (p. 207).
■hCG is administered for luteal phase support especially when GnRH agonist is used.
■Treatment of male infertility (hypogonadotropic hypogonadism) (p. 201).
■Treatment of cryptorchidism.
Hypogonadotropic hypogonadism (WHO Group-I, p. 212) with or without amenorrhea.
■Failed clomiphene induction especially in patients with PCOS.
■Unexplained infertility.
Contraindications
High level of endogenous FSH, indicating ovarian failure (p. 287 and 294)
■Overt thyroid or adrenal dysfunction
■Pituitary tumor
■Indeterminate uterine bleeding.
Gonadotropins
Treatment protocol
Management options
Results of Gonadotropin Uses.
Treatment Protocol
The drug dose schedule should be individualized to get the best result As a rule, a higher dose is required in cases of secondary amenorrhea due to pituitary failure) and a smaller dose may be required in ovulatory failure or corpus luteal insufficiency
Women with hypogonadotropic hypogonadism should be treated with hMG (FSH and LH) Treatment with hMG begins following spontaneous menses or induced withdrawal bleeding. A daily dose of 1-2 ampoules of hMG is given intramuscularly for at least 5 days and continued thereafter, with the same dose or an increasing dose with cervical mucus study. E, estimation and sonographic (transvaginal) folliculometry at interval of 2-3 days or earlier until the preovulatory follicular diameter measures 18-20 mm (p. 207 and 208). The hMG is then discontinued and after 24 hours, hCG is given intramuscularly for ovulation. The dose of hCG is 5,000 IU for induction of ovulation. The patient is advised to have sexual intercourse on a number of occasions over the next 36-72 hours progesterone support.
In some cases, for adequate ovarian follicular growth, high doses of FSH (4-6 ampoules per day) may be needed. High responders are those women who have exagger- ated response in follicular development. The diagnostic features are enlarged ovaries with large number of folli- cles, elevated serum estradiol (>3,000 pg/mL).
Management Options
■Coasting
To continue GnRH agonist.
• No gonadotropin stimulation.
• To give hCG once estradiol level is within the normal range (see above).
■ Oocyte retrieval and fertilization-freezing all embryos and no transfer to avoid ovarian hyperstimulation syndrome (OHSS).
■To delay embryo transfer until the symptoms subside. To cancel the treatment cycle.
These women have good prognosis in subsequent cycles.
Poor responders are those women who develop fewer follicle (<3) and have serum estradiol <500 pg/mL in spite of high doses of gonadotropins.
Management Options
■To use higher doses of gonadotropin stimulation.
To decrease the doses of GnRH agonist.
To use GnRH antagonist instead of long-acting agonist. These women have relatively poor prognosis.
Results of Gonadotropin Uses
Cumulative pregnancy rate is about 90% after 6 cycles treatment. Spontaneous miscarriage rate is high (20%). Risk of ectopic pregnancy is high. Multiple pregnancy rate is between 10 and 30%. Majority are twins. There is no increased incidence of congenital malformation of the fetus.
Ovarian reserve means the quantity as well as quality of follicles present in the ovary. The total number of oocytes declines with the age of a woman since her birth. Inhibin B secreted by the competent follicles, exerts negative feedback on pituitary FSH secretion (p. 62). With the progressive fall in follicle number as with age, inhibin B level is reduced. There is rise in FSH level even in the early follicular phase.
■ Detection of diminished ovarian reserve (DOR): Tests for detection of DOR can indentify the women who are likely to have poor response with gonadotropin and lower pregnancy rate:
• Levels of cycle D3 serum FSH >10-15 IU/L.
• Levels of D, serum estradiol >60-80 pg/mL.
Clomiphene citrate challenge test: Levels of D, serum FSH and estradiol are measured. The women is given clomiphene citrate (100 mg daily from D₃-D,). Serum levels of FSH is measured again on D10 and elevated values of serum FSH (more than 2 SD of the mean) are obtained.
• Levels of serum anti-Müllerian hormone (AMH)- low (0.2-0.7 ng/mL).
• Levels of basal serum inhibin B-low (<40 pg/mL). However, it is not a reliable measure.
• Antral follicle count (AFC): Total number of antral follicles (measuring 2-10 mm) in both the ovaries using transvaginal sonography (TVS) is proportional to the number of primordial follicles present in the ovaries. So, a low AFC indicates poor ovarian reserve. A woman in her reproductive age, usually have 20-150 growing follicles in the ovaries at any time. A count of <10 predicts poor reserve.
■Ovarian volume measurement (OVM): Ovarian volume decreases with progressive follicular loss. Poor ovarian reserve indicates poor outcome with IVF. Women need counseling for alternatives like donor oocyte or adoption.
OHSS
Risk factors for OHSS
Pathophysiology
Prevention
Classification of OHSS
Management
Ovarian Hyperstimulation Syndrome The OHSS is characterized by multiple follicular development and ovarian enlargement following hCG stimulation. It occurs mostly with the conception cycle. The clinical features appear about 3-6 days after the ovulating dose of hCG is administered. It is an iatrogenic and potentially a life-threatening complication of superovulation.
Risk Factors for OHSS
Young age <30 years, PCOS, serum E2 >2,500 pg/mL, rapidly rising serum E₂ levels (>75% rise from previous day), ovarian ‘necklace sign’ on USG (multiple small follicles) (Fig. 32.1) hCG administration, and multiple pregnancy.
Pathophysiology
This is poorly understood. Increased capillary permeability leads to leakage of fluid from the peritoneal and ovarian surfaces. Variety of chemical mediators like cytokines, vascular epidermal growth factor (VEGF), prorenin, renin, and nitric oxide (NO) system are thought to be stimulated with hCG administration.
Prevention
Complete prevention may not be possible but severity can be reduced (Table 32.3). The important steps to be taken are:
■Use of GnRH antagonists for pituitary downregulation.
■Low starting dose of gonadotropins in high-risk women.
■Metformin cotreatment during gonadotropin stimula- tion in women with PCOS.
■Close monitoring of the superovulation cycles using TVS and serum estradiol estimation (p. 207).
■To withhold ovulatory dose of hCG in susceptible cases and to cancel the cycle or to delay the dose of hCG injection (coasting).
■Follicular aspiration after hCG administration and cryopreservation of oocytes or embryos for future use may reduce the severity of symptoms (coasting and cryopreservation).
Dopamine agoinst: Cabergoline is found to be effective as it inhibits the action of VEGF.
Aspiration of immature oocytes and in vitro maturation (IVM) are done. Subsequently intracytoplasmic sperm injection (ICSI) is performed on IVM oocytes and embryos are transferred to the hormonally prepared uterus.
Progesterone should be used for luteal phase support (p. 208) instead of hCG.
Management
Management of OHSS is mainly supportive. Moderate and severe cases are to be admitted.
To monitor complete hemogram, liver function tests (LFTs), renal function tests (RFTs), electrolytes, coagulation profile, electrocardiography (ECG), and urine output.
Chest X-ray (shielding the pelvis), monitoring of O, saturation is needed when there is respiratory compromise.
③ TVS is to be done to assess ovarian volume and ascites.
Oral fluid is continued to prevent hemoconcentration and to maintain renal perfusion. Normal saline 150 mL/hour IV is given when hematocrit is >45%.
To relieve respiratory distress, abdominal paracentesis may be done under USG guidance.
Human albumin (50 mL of 25%) may be administered to correct hypovolemia. It may be repeated.
Pain is controlled with paracetamol or pethidine. Intensive care management (ICM) is needed for specific complications like renal failure.
Surgery is rarely indicated.
AntiGonadotropins
1. Danazol
Mode of action
Indications of Danazol
Precaution
Dose
Side effects
2. Gestrinone
Dose
Side effects
ANTIGONADOTROPINS
Commonly used drugs
■Danazol
■Gestrinone
Danazol
Danazol is an isoxazole derivative of 17-alpha ethinyl testosterone. It has got both androgenic and anabolic properties. It is strictly antigonadotropin but acts as an androgen agonist (Table 32.4).
Mode of Action
The mechanism of action is complex and includes the following:
Acting on the hypothalamo-pituitary-gonadal axis → depression of frequency of GnRH pulses → suppression of pituitary FSH and LH surge. There is, however, no change in the basal gonadotropin level. Due to this reason the word ‘pseudomenopause’ seems misnomer; while the estrogen level is reduced but unlike menopause, the gonadotropins remain static in base levels.
Reduces the liver synthesis of sex hormone-binding globulin (SHBG) and as such, free testosterone is increased which in turn has got direct action on endometrial atrophy.
■Acts directly on the ovaries, inhibiting the enzymes
responsible for steroidogenesis. Estrogen level is low. ■Binds with steroid receptors on the endometrium and also in the ectopic endometrial sites.
■It causes endometrial atrophy
■Immunologic effects of danazol include decrease in serum immunoglobulins (Igs), interleukin-1 (Il-1) and tumor necrosis factor (TNF) production. This effect helps in the regression of endometriosis.
The net result is production of an hypoestrogenic and hyperandrogenic and anabolic state.
Indications of danazol.
- Endometriosis
- DUB (menorrhagia)
- Symptomatic fibroid
- Precocious puberty
- PMS/PMDD (p. 150)
- Benign fibrocystic disease of the breasts (breast pain)
7.Prior to hysteroscopic endometrial ablation, to make the endometrium thin.
Precautions
It should be commenced in the early follicular phase of the menstrual cycle. Barrier method of contraception should be used to avoid being administered during early pregnancy following accidental ovulation. There is a chance of virilization of the female offspring. It is contraindicated in liver disease.
Dose
Depending upon the indication and response, the dose varies from 200-800 mg daily orally. It is used less commonly.
Lower doses of 100 mg/day is also used. Duration of therapy is usually 4-6 months. Improvement following treatment is about 90%. Recurrence rate is 15-30% within 2 years of therapy. Therapeutic effectiveness of danazol with GnRH agonist appear to be the same.
Side Effects (Table 32.5)
The side effects are mostly related to hypoestrogenic and androgenic activity. However, most of these effects revert back to normal soon following stoppage of the therapy. It is recommended that the patient should discontinue the treatment, if they develop hirsutism or hoarseness of voice.
Gestrinone
Gestrinone is a derivative of 19-norethisterone. It is an androgen-agonist and progesterone agonist-antagonist. It markedly reduces SHBG levels and thus increases the free testosterone. It reduces the secretion of FSH and LH. It has a much longer half-life and the dose required to produce equivalent results, is much smaller than danazol.
Dose
2.5 mg twice weekly starting on first day of cycle with second dose 3 days later, repeated on same two days preferably at same time each week.
Side Effects
This are the same to those of danazol but usually less marked.
Gonadal Hormones?
Mechanism of Action?
GONADAL HORMONES
There are three gonadal steroid hormones. These are estrogen, progesterone, and androgen.
MECHANISM OF ACTION
Steroid sex hormones are well-absorbed through the skin and the gut. While most are subjected to extensive hepatic metabolic inactivation, there is some enterohepatic recirculation especially of estrogens. This circulation may be interrupted by diarrhea to cause loss of efficacy. The sex hormones are transported in the blood non-specifically by albumin and specifically by SHBG.
Steroid hormone receptors are complex proteins inside the target cell. The steroid penetrates the cell membrane and mediates action via receptors within the nucleus in the cytoplasm (Fig. 7.6).
Estrogens
Preparation available?
Replacement Therapy
Pharmacotherapy: Indications of of only Estrogen Therapy?
Adverse effects?
ESTROGENS
Natural estrogens are 18-carbon atom steroids. Estradiol is the most active natural estrogen in human uses. Clinical and metabolic effects of estrogens and their grades of potency are different (Table 32.6).
Preparations Available
■ Natural
■ Synthetic
Natural
(a) It is available in the form of water soluble conjugated estrogen as Premarin [conjugated equine estrogen (CEE)]. It is obtained from the urine of pregnant mares. It is available as tablets 0.3 mg, 0.625 mg, and 1.25 mg and as injection of 20 mg ampoules for IM or IV injection.
(b) Estradiol valerate used for priming the endometrium in donor oocyte program (Ch. 17).
Synthetic
■Oral
■ Pessary
■ Injectable
■ Implant
■Cream/gel
■Patch
Oral: This is the best route for synthetic preparations.
commonly used
- Ethinyl estradiol (Lynoral): 0.01 mg and 0.05 mg daily is
- Estradiol valerate: 1-2 mg
3 CEE: 0.3 or 0.625 mg
4 ■Estriol succinate (Evalon): 1-2 mg.
Injectable: (a) Estradiol ester as progynon depot (Schering): 10 mg ampoule Estradiol benzoate or dipropionate: 1 mg and 5 mg ampoule.
Cream: (a) Vaginal cream-dienestrol (0.1 mg/g), estriol (1 mg/g); (b) Percutaneous cream delivers 3 mg of estradiol in each daily 5 g applicator of cream.
Gel: 17ẞ-estradiol gel, 1 mg to be applied once daily over the skin of the lower trunk.
Pessary: Dienestrol or estradiol acetate pessary (inserted for 90 days).
Implants: Subcutaneous implants of 50 mg and 100 mg of 178-estradiol effect lasts for 6 months.
Transdermal patch: It contains 17ẞ-estradiol releasing about 0.05-0.1 mg of estradiol in 24 hours. Patch should be applied below the waist line and changed twice a week.
Therapy
■Replacement therapy
■Pharmacotherapy
Replacement Therapy
Ovarian hypofunction: Estrogen daily × 21 days followed by norethisterone or medroxyprogesterone 5 mg x last 10 days (p. 373).
Menopausal symptoms:
■Cyclic or continuous therapy in the form of estradiol or conjugated estrogens
■Postmenopausal hormone replacement therapy (HRT) in a symptomatic women (p. 50)
⚫⚫ To reduce vasomotor symptoms
• To prevent osteoporosis
• To prevent cardiovascular disease.
It is administered either cyclic or continuous. Progestogen should be added to reduce endometrial Carcinoma. However, in hysterectomized individuals, progestogen is not added. It is especially indicated in premature ovarian failure (POF), gonadal dysgenesis and in surgical menopause (details in Ch. 6).
■ Genitourinary symptoms of menopause is observed when serum estradiol level is <35 pg/mL.
■Common symptoms are:
Vaginal dryness, burning and irritation
Sexual difficulty due to lack of lubrication, causing pain
• Urinary symptoms: Urgency, dysuria and recurrent UTI. Treatment options are: To use local estrogens in the form of vaginal cream, tablet, ring or oral tablets. Commonly used estrogens are: Conjugated estrogens or 17 ẞ-estradiol.
Pharmacotherapy
The estrogen is most commonly used along with progestogen and as such, the use of the combined therapy is discussed later on.
The indications of only the estrogen therapy are mentioned here.
Oral contraception
While the combined estrogen and progestogen prepara- tions are widely used throughout the globe, estrogen in isolation is only used as postcoital contraception (details in Ch. 30).
Vaginitis
Senle or atrophic vaginitis-either vaginal cream or oral estrogens may be equally effective (Ch. 6).
Vuovaginitis
Vuwaginitis in childhood, foreign body in the vagina orxual assault-low dose of oral estrogen or vaginal cream helps in increasing the vaginal defense and hastens recovery (p. 457).
Intersex state
In urner’s syndrome (45, XO) or gonadal dysgenesis (46, XY), estrogen therapy is helpful for the growth and development of the secondary sexual characters (Ch. 28).
In androgen insensitivity syndrome (46, XY), after gonadectomy supplementary estrogen therapy is indicated to prevent regression of the breast development, osteoporosis and cardiovascular complications (Ch. 28).
The estrogen is used cyclically as ethinyl estradiol 0.01 mg twice daily for 25 days. However, in prolonged use, progestogen in the form of medroxyprogesterone acetate 10 mg daily is added from day 16-25, to minimize the adverse effects of estrogen. Alternatively, a combined oral ‘pill’ may be prescribed.
Dysfunctional uterine bleeding
The estrogen in pharmacological doses causes rapid growth of endometrium. As such, acute bleeding can be stopped by oral conjugated estrogen in a dose of 10 ing a day. The bleeding usually stops within 24 hours. Alternatively, 25 mg may be given intravenously every 4 hours for 3 doses (p. 159).
Delayed puberty
If the breast development fails to start even at the age of 14, 10 µg of estrogen daily may be of help. In cases of irregular bleeding or when the breast development is well- advanced, progestogens may be added (Ch. 5).
Cervical mucus hostility
To improve the quality of the cervical mucus in infertility, low dose of estrogen (ethinyl estradiol 0.01 mg) may be given cyclically, from day 1-14.
An Adjunct with Clomiphene Therapy
In cases of hypoestrogenic state with hypomenorrhea, small dose of estrogen is of help to improve the quality of the cervical mucus.
Genuine stress incontinence (GSI) in postmenopausal women to improve the tone of collagen tissue.
Comments
Oral route with preparations of ethinyl estradiol is widely used because of its efficacy, low cost, and minimal intoler- ance. Vaginal cream used in atrophic vaginitis has got its local and systemic effects.
Intramuscular (IM) administration of progynon depot 10 mg at interval of one month is helpful as a prophylaxis against postmenopausal symptoms, following hysterectomy with bilateral salpingo-oophorectomy in premenopausal women.
Adverse Effects
Minor ailments are:
■Nausea, vomiting
■Breast tenderness
■Breakthrough bleeding
■Weight gain
Major effects include: Increased incidence of endome- trial carcinoma, thromboembolism, cerebral thrombosis, and hemorrhage.
To minimize breakthrough bleeding and prevent endometrial carcinomas and vascular complications, progestogens should be combined with estrogen therapy.
Contraindications of use are important (Table 32.7).
AntiEstrogens
1. Clomiphene:
MOA?
INDICATIONS?
Mode of Adminstration?
CONTRA-INDICATIONS?
SIDE EFFECTS?
RESULTS?
ANTIESTROGEN
■ Clomiphene
■Tamoxifen
■Aromatase inhibitors
Clomiphene
Clomiphene citrate is a nonsteroid triphenylethylene compound with a structure similar to that of stilbestrol. The commercially available form is a mixture of two isomers, enclomiphene-a potent antiestrogen and zuclomiphene-a weak antiestrogen.
Mode of Action
In the hypothalamus, clomiphene citrate binds to estrogen receptors, occupies the nuclear site for a long time (weeks). The negative feedback of endogenous estrogen is thus prevented. The frequency of pulsatile GnRH secretion is thereby increased which in turn results in rise of pulse frequency of both LH and FSH. Antiestrogenic effects are observed at the level of cervix and endometrium.
During therapy with clomiphene citrate (CC), there is rise in serum levels of LH and FSH and also the levels of serum E2.
Indications
■ Anovulatory infertility where other factors have been excluded.
■Induction of ovulation-the ideal case is one of normogonadotropic-normoprolactinemic disorders of ovulation.
■Assisted reproductive techniques in producing supero- vulation.
■Male infertility with defective spermatogenesis due to hypogonadotropic hypogonadism.
Mode of Administration
Adjuvant drugs: Adjuvant drugs are used when there is failure with clomiphene therapy (Ch. 17).
Contraindications
■Patients who are hypogonadotropic and hypoestro- genic.
■Presence of cystic ovaries.
Side Effects
These include visual disturbances, headache, hot flashes, breast tenderness, abdominal discomfort, loss of hair, rashes, ovarian enlargement and multiple pregnancy. Hyperstimulation syndrome (p. 444) is less likely.
Results
While successful induction can be achieved by 90%, pregnancy rate is about 50%. The reduced pregnancy rate may be due to its antiestrogenic effect on endometrium cervical mucus and the oocyte. There may be the presence of other factors for infertility including luteal phase defect (LPD) and luteinized unruptured follicle (LUF) (p. 197). Chance of multiple pregnancy ranges 0-5%.
AntiEstrogens
2. Aromatase Inhibitors:
Letrozole & Anastrozole.
3. Tamoxifen [SERMs]
Aromatase Inhibitors
It inhibits the enzyme aromatase in the granulosa cells of ovarian follicles (p.61 and 62). It suppresses estrogen (E) synthesis. It increases the level of FSH. Intra-ovarian androgen levels are also increased. This enhances sensitivity to FSH. No differences in adverse effect or congenital anomalies when compared to CC. Letrozole in combination with gonadotropins may be used in poor responders for IVF. Letrozole, 2.5 mg given from D3 to D7 increases the
release of gonadotropins from the pituitary and stimulates development of ovarian follicle. It suppresses ovarian estradiol secretion and reduces estrogen induced negative feedback. As a result, levels of FSH rises. Intraovarian androgens are increased which increase FSH sensitivity. As opposed to clomiphene, it has no peripheral antiestrogenic effects on the endometrium and the cervical mucus. Half-life of letrozole is 45 hours. Letrozole is used either as a firstline therapy (alternative to clomiphene) or in clomiphene-resistant women (p. 203) with anovulatory infertility. Pregnancy rates are comparable or better than that of clomiphene. Multiple pregnancy rates are low (monofollicular development).
Anastrozole, another aromatase inhibitor is found to be effective in reducing the growth of pelvic endometriosis and in pain relief.
Aromatase inhibitors are primarily used for the treatment of breast cancer in postmenopausal women.
Tamoxifen (SERMS)
Tamoxifen [selective estrogen receptor modulators (SERMs)], is similar to clomiphene both structurally and functionally. It has got both estrogen antagonist and agonist effects.
It is a competitive inhibitor to estrogen at the receptor site. Antiestrogenic function of raloxifene is more selective in uterus and breasts.
■It decreases antithrombin III and increases the SHBG level (agonist action). Venous thromboembolism (VTE) is increased,
■It can be used for induction of ovulation in doses of 20 mg per day for 5 days, in cases of intolerance to clomiphene.
■It is widely used for the treatment of benign breast diseases,
In postmenopausal breast carcinoma, it is given in doses of 10 mg twice daily for 2 years as an adjuvant therapy. It is effective both in estrogen receptor positive and negative cases.
■In recurrent endometrial carcinoma, it inhibits the binding of estradiol to the estrogen receptor. Tamoxifen increases the progesterone receptors. A dose of 20-40 mg per day has been used. Low grade tumors and hormone receptor positive tumors have got better response.
■Raloxifene (p. 50) therapy (60 mg a day) is effective in regression of endometriosis.
Bazedoxifene (BZA) is a SERM. It is used in combination with CEE to improve the vasomotor symptoms and prevents postmenstrual bone loss. Combination of CEE (0.45 mg) PLUS BZA (20 mg) do not cause change in breast density and endometrial thickness.
Side Effects
Hot flashes, vaginal dryness, risks of thromboembolism and risks of endometrial carcinoma on prolonged use.
Progesterone
Diagnostic Indications
Therapeutic Indications
Metabolic effects
PROGESTERONE
Progesterone is a natural hormone (C-21 steroid) pro- duced mainly by the theca lutein cells of the corpus luteum (p. 71). It is also secreted by the adrenal cortex in small amount. During pregnancy, placenta is the main source. Progesterone produces secretory changes in an estrogen primed endometrium. Natural progesterones are rapidly metabolized and inactivated when admin- istered by the oral route and as such, it is to be used parenterally. During the last few decades, a number of compounds were synthesized having the properties of progesterone and could be given in tablet form. These are called progestational agents, gestagens, pro- gestogens or progestins. Classification of progestogens and their grades of progestational activity are given in Tables 32.8 and 32.9.
Uses
- Diagnostic
■ Therapeutic
Diagnostic
Progesterone challenge test: In the investigation of pathological amenorrhea, this test is employed. If with- drawal bleeding occurs, it proves (a) Intact HPO axis; (b) There is adequate endogenous estrogen (>40 pg/ mL); (c) The endometrium is responsive; and (d) The uterovaginal canal is patent. The individual is likely to respond to ovulation induction drugs (p. 395).
Dose
Medroxyprogesterone acetate 10 mg daily for 5 days is given orally.
Limitations of the test
Some women may bleed with fluctuating levels of estrogen as in hypothalamic amenorrhea or in early stages of POF. Secondly women with high androgen levels (PCOS and CAH) may have atrophic endometrium and may fail to bleed.
Therapeutic Indications
Contraception
Combined preparations of estrogen and progestogen are widely used as contraceptive pill (Ch. 30). Uses of only
progestogens as contraception are:
Minipill (oral) (p. 410)
■Levonorgestrel: Emergency.contraception (p. 411).
Depot medroxyprogesterone acetate (DMPA) (injec- table)
Norethisterone enanthate: NET-EN (injectable)
Implant (implanon subdermally) (p. 411)
Vaginal ring containing levonorgestrel (p. 423)
Levonorgestrel-intrauterine system containing L-norgestrel (p. 398). (LNG-IUS)-
Dysfunctional uterine bleeding
Progestogen administration will cause secretory changes in the endometrium. Thus, it is very active in cases of ano- vulatory than in an ovulatory DUB. The therapy is ideal in puberty, adolescent and those approaching menopause.
To stop bleeding, norethisterone or norethisterone acetate 5 mg thrice daily is quite effective. To regulate the cycle, the same preparation is used from D5-D25 or from D15-D25 of cycle.
Mode of action
Progesterone decreases synthesis of estrogen receptors
the endometrium.
It converts estradiol to less potent estrone through enzymatic action.
It inhibits mitotic activity of the endometrial cells.
It induces the enzyme estradiol dehydrogenase- which degrades estradiol in the endometrium.
Over all progesterone acts as an antiestrogen on the endometrium.
Endometriosis
The use of progestogens induces a hyperprogestogenic- hypoestrogenic state. Progestogens cause decidualization of endometrial tissue. There will be atrophy of the glands, fibrosis and atrophy of the ectopic endometrial tissues. Progestins also reduce the nerve fiber density and nerve growth factor expression in endometriotic lesions.
The drugs commonly used are medroxyprogesterone acetate or dydrogesterone or derivatives of 19-norethister- one.
Dose
Norethisterone 5 mg or medroxyprogesterone 10 mg twice or thrice daily and continued for 6-9 months. The patient remains amenorrheic.
Alternatively, IM injection of medroxyprogesterone acetate 100 mg every 2 weeks for 4 doses and then 200 mg every month for 4 doses will produce amenorrhea. This is suitable in cases of older women who have completed family.
Dysmenorrhea
Dydrogesterone 5 mg starting from day 5 for 20 days, relieves dysmenorrhea probably by inhibiting uterine contractions. The ovulation is not suppressed. Use of LNG-IUD and progestin implant (implanon) is Found to be effective in cases with pelvic endometriosis or adenomyosis.
Luteal phase defect (LPD) (p. 203)
In a proven case, daily IM injection of 12.5 mg progesterone in oil, beginning 2-3 days after the ovulation until menstruation occurs or if conception has taken place, until 10-12 weeks of gestation. Micronized progesterone 100 mg thrice daily can be administered either vaginally or orally. Vaginal suppositories 25 mg twice daily starting 2-3 days after the BBT rise is equally effective.
Endometrial hyperplasia and endometrial carcinoma
Its role in endometrial carcinoma depends on the number of steroid receptors on the tumor. Well-differentiated grade I endometrial carcinoma has got the highest number of receptors. These cases are suitable for progestogen therapy. Recurrent endometrial carcinoma having good steroid receptor status is also suitable.
Dose
17a-hydroxyprogesterone caproate 1,000 mg IM daily for 1 week, weekly for 3 months and thereafter at interval of 2 weeks for 1 year. Alternatively, medroxyprogesterone acetate 400 mg IM weekly for 3 months and then every 2 weeks for 1 year.
Premenstrual syndrome (PMS) (p. 150)
Controversy exists with the hypothesis that progesterone deficiency may be the cause. So, progestogens have been tried to relieve the symptoms. Dydrogesterone 5 mg twice daily from day 5 for 20 days in each cycle for 3-6 cycles may be tried.
Luteal support
It is usually given on the day after oocyte retrieval for ART (p. 208). Progesterone is used in any of these forms.
■Vaginal suppository 200 mg twice daily
■ Micronized progesterone orally 200 mg twice daily. It is
usually continued for about 14 days (p. 208).
■Progesterone in oil 50 mg IM daily
Postponement of menstruation
In order to post-pone the menstruation, norethisterone preparation 5 mg tablet thrice daily is to be taken at least 3 days prior to the expected date of menstruation. This should be continued till such time when the patient wishes to have her period. The period usually starts after 48-72 hours. This should not be taken casually, as it may disturb the menstrual pattern. There is no contraceptive protection during the period of intake of medicine.
Hormone replacement therapy (HRT)
Progestins are combined with estrogen as an HRT for postmenopausal woman whose uterus is present. This prevents endometrial hyperplasia. They can be used cyclically for last 12-14 days of the cycle or continuously with estrogen (p. 50).
Side Effects
Progestogens side effects are as mentioned in Table 32.10.
Metabolic effects of progestogens and their grades of progestational activity.
Uses of hormones in gynecology ?
