Advances In Reproductive Endocrinology
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ADVANCES IN REPRODUCTIVE ENDOCRINOLOGY Professor Adeyemi O. Adekunle Department of Obstetrics and Gynaecology College of Medicine, University of Ibadan University College Hospital, Ibadan, Nigeria. Adekunle A.O.
1
Advances in Reproductive Endocrinology : Enabling Objectives
Mention the various advances that occurred in Reproductive Endocrinology in the past two decades;
Describe the recent advances in Hormone Replacement Therapy, hormonal contraception and ovulation induction
Comment on the role of steroids in the management of pre-maturity.
List the role of prostaglandins in induction of labour and management of post-partum haemorrhage;
Comment on antiprogestins and abortions. Adekunle A.O.
2
Introduction
Normal reproductive function depends on complex hormonal communication between endocrine and target organs.
Normal function is essential to sexual development at puberty and to the cyclical processes of ovulation and menstruation.
Recent advances in reproductive endocrinology have provided treatment for disease conditions that hitherto could not be managed.
Similarly, these advances have led to introduction of new products for managing gynaecologic and obstetric conditions. Adekunle A.O.
3
Advances in Reproductive Endocrinology
Major advances have occurred in the following areas:
GYNAECOLOGY Hormone Replacement Therapy (HRT) -New routes of administration
Contraception –new, long acting, highly effective methods
Management of infertility – use of GnRH agonists and antagonists in ovulation induction. Adekunle A.O.
4
Recent Advances in Reproductive Endocrinology OBSTETRICS
Prostaglandins Induction of labour Control of post-partum haemorrhage
Antiprogestins In management of abortions
Ante-natal Steroids In the management of pre-term labour Adekunle A.O.
5
Advances in Hormone Replacement Therapy
Oral therapy is the most suitable initial therapy for most women but due to extensive metabolism, only about 10% reach the systemic circulation.
Thus the dose of administered estrogen has to be correspondingly high to achieve effective blood levels.
There is also wide variation in absorption and metabolism during the first pass of intestine/liver.
The so called “first pass” effect has various clinical implications and has led to the introduction of other routes of administration. Adekunle A.O.
6
Transdermal Estrogen
Estrogen has been found to be well absorbed through the skin and subcutaneous fat as well as vaginal epithelium, nasal and sublingual mucosa.
Metabolism in the intestine is avoided.
Pure estradiol can, therefore, be administered directly into the systemic circulation causing a significant rise and an estradiol:estrone ratio similar to that found in premenopausal women Adekunle A.O.
7
ESTRADIOL PATCHES
A patch consists of single transparent matrix with an adhesive layer which contains estradiol.
The dose required is proportionate to the surface area of the patch in contact with the skin.
Cannot be re-applied after being taken off the skin, so it should and need not be taken off prior to bathing.
Changed twice weekly, newer ones last 7 days. Adekunle A.O.
8
ESTRADIOL PATCHES ADVANTAGES
Low dose pure estradiol;
DISADVANTAGES
Local skin reactions; More expensive than tablets;
Avoids intestine and liver metabolism;
Physiological estradiol:estrone ratio;
Not well tolerated in warm climate;
Variable absorption.
Reduces serum triglyceride;
Few side effects. Adekunle A.O.
9
ESTRADIOL GEL
Application of gel containing estradiol;
Hydro-alcoholic gel containing 0.06% w/w 17 β-estradiol ;
Absorption through the skin is rapid while the alcohol evaporates and effective blood levels are obtained;
However, variations in size of the application area may have impact on absorption and the subsequent levels of circulating esradiol;
This route of administration allows the woman a feeling of greater control. Adekunle A.O.
10
ESTRADIOL IMPLANTS
Insertion of pellets of crystalloid estradiol.
Not widely used;
Insertion of the pellets requires a minor surgical procedure –easy, takes only 3 – 4 minutes and is safe.
Pellets of estradiol are available in 25, 50 and 100 mg doses.
The 50 mg dose is most commonly used for HRT and is given at 6 monthly intervals. Adekunle A.O.
11
ESTRADIOL IMPLANTS (Contd.) ADVANTAGES
DISADVANTAGES
Pure estradiol;
Surgical procedure;
Six monthly insertion;
High levels of estradiol in circulation;
Unable to control absorption;
Risk of supraphysiological blood levels;
Difficult to remove pellet; Prolonged release of estradiol
Avoids “first pass” effects; Physiological estradiol:estrone ratio.
Adekunle A.O.
12
ADDITIONAL PROGESTIN
The need to give additional progestin is well established and accepted for women with a uterus;
Until recently, only suitable by the oral route;
Recent advances have produced separate routes.
Adekunle A.O.
13
ROUTES FOR ADDITIONAL PROGESTIN
Progestin can now be incorporated in some matrix patch preparations;
Natural progestin can also be administered via vagina as pessary (avoids first pass hepatic and intestinal metabolism ==> reduced side effects;
Intra-uterine progesterone can be given through an intrauterine device (IUD), e.g., Minera. Adekunle A.O.
14
ADVANCES IN HORMONAL CONTRACEPTION
Major advances have been made in the production of long-lasting and highly effective methods:
Oral Contraceptives
Injectables
Implants
Contraceptive Rings
Emergency Contraceptives Adekunle A.O.
15
ORAL CONTRACEPTIVES
Three new compounds are now widely used:
Combined oral contraceptives containing these progestins have shown almost no adverse changes in:
Norgestimate NG) Gestodene (GD), and Desogestrel (DG).
Carbohydrate and lipid metabolism, Haemostatic system.
They also have less androgenic effects. Adekunle A.O.
16
INJECTABLES
Available formulations (DMPA and NET-EN) are highly effective, long-lasting, safe and reversible.
However, they have high discontinuation rates – menstrual irregularities being the most frequent.
Addition of a short- or medium-acting estrogen into progestin preparations could result in an improvement of endometrial bleeding pattern. Adekunle A.O.
17
NEW INJECTABLES (Contd.)
This has enabled the development of once-amonth injectable contraceptives of:
High efficacy
With bleeding patterns resembling those of the normal menstrual cycle.
The estradiol in these new formulations (cypionate and valerate) are short-acting, yielding elevated serum levels of estradiol for no more than 15 days. Adekunle A.O.
18
NEW INJECTABLES (Contd.) CYCLOFEM
Contains low doses of medroxyprogesterone acetate (25 mg) and estradiol cypionate (5 mg).
MESYGINA
Contains low doses of NET-EN (50 mg) and estradiol valerate (5 mg).
Both preparations have proved their high efficacy in large multicentre studies. Adekunle A.O.
19
IMPLANTS
The observation that steroid hormones can be released at a constant rate from silicone rubber for long periods of time led to the development of subdermal implants for contraception in humans.
The last two decades have witnessed great strides in the development of several types of subdermal implant systems.
Basically, two groups have emerged: Biodegradable Implants Non-biodegradable Implants Adekunle A.O.
20
NEW IMPLANTS JADELLE
2-implant system, designed to release the same amount of levonorgestrel as Norplant;
Accomplished through a modification in the design of the implant, which consists of an inner rod containing a mixture of 50% levonorgestrel and 50% silastic membrane. IMPLANON (Organon)
Single implant containing 3-keto-desogestrel, the major metabolite of progestin desogestrel. Adekunle A.O.
21
NEW IMPLANTS (Contd.) ST 1435 (NESTERONE) IMPLANT
Single implant system that releases the synthetic progestin ST 1435 (16-methylene-17acetoxy-19 norprogesterone);
Designed for two years;
Not biologically active when taken orally, thus permits the use of implant in nursing mothers. ANNUELLE (NET Implant)
Consists of 4 – 5 small pellets made of 90% norethidrone (NET) and 10% cholesterol.
Effective for 1 year, Non-biodegradable. Adekunle A.O.
22
Levonorgestrel Intrauterine System (MirenaTM)
A T-shaped polyethylene device.
The frame is 32 millimeter in both the horizontal and the vertical directions.
The cylindrical reservoir around the vertical stem contains a mixture of silicone and 52 mg of levonorgestrel, a progestin widely used in implants, oral contraceptives, and vaginal rings.
25 microgram of levonorgestrel is released every day.
A monofilament removal thread is attached to a loop at the end of the vertical stem. Adekunle A.O.
23
Levonorgestrel Intrauterine System TM (Mirena )
Mirena has many advantages over the copper IUDs.
It is highly effective with the first year failure rate of 0.1 percent and five year cumulative failure rate of 0.7 percent.
There is a marked reduction in menstrual blood loss and the systemic level of hormone is very low as compared to the other progesterone-only methods.
Unlike copper IUDs, Mirena provides dramatic relief in dysmenorrhea Adekunle A.O.
24
Levonorgestrel Intrauterine System TM (Mirena )
Once inserted it is effective for 5 years and fertility returns rapidly on discontinuation. Eighty percent of the women intending to get pregnant will become pregnant within 12 months of discontinuing Mirena.
Mirena has many non-contraceptive benefits:
It has beneficial effect on menorrhagia and dysmenorrhea, Reduces the risk of pelvic inflammatory disease, It also reduces the risk of endometrial cancer by 50% Adekunle A.O.
25
CONTRACEPTIVE VAGINAL RINGS
Hormones diffuse continuously from a reservoir within a ring inserted into the vagina.
Convenient, does not require daily administration or attention;
Entirely under the control of the client;
Steady blood levels of steroids allows a greater contraceptive effect from a low-dose steroid.
Rings come both as combined formulations – containing progestin and estrogen - and as progestin-only formulations. Adekunle A.O.
26
MALE HORMONAL CONTRACEPTION
Testosterone or a combination of testosterone and progestin is used to suppress sperm production;
When testosterone is administered, the levels are lowered in the testes, resulting in reduced sperm production.
Pills, patches, injections, and implants have been tested to deliver various formulations of testosterone.
Injected formulations appear to be the most effective in suppressing sperm production. Adekunle A.O.
27
ADVANCES IN OVULATION INDUCTION
A better understanding of the hormonal control of human folliculogenesis has allowed physicians to use ovarian stimulation in every clinical situation where the main goal is to achieve pregnancy.
Controlled ovarian stimulation (COH) has increasingly become a new tool in many situations.
These include the use of GnRH Analogues – peptides in which the primary structure of GnRH has been altered by the deletion or substitution of one or more amino acids. Adekunle A.O.
28
GnRH Agonists (GnRH-a)
Ability of GnRH agonists to suppress LH concentration before and during ovarian stimulation has earned them an undisputed place in IVF treatment protocols. FORMULATIONS AVAILABLE
Buserelin, Leuprolide, Goserelin, Histrelin, Triptorelin; single dose subcut.
Buserelin, Nafarelin 2-4 times daily as nasal spray. Absoption into systemic circulation is poor.
Leuprolide, Triptorelin I.M. monthly as depot preparation (endometriosis and fibroids) Adekunle A.O.
29
GnRH Antagonists
GnRH antagonists are synthetic analogues of GnRH that compete with endogenous GnRH for pituitary binding sites but are unable to induce GnRH receptor cross-linking;
This process appears to be necessary to effect calcium ion-mediated gonadotrophin release.
Antagonists suppress GnRH release within a few hours, have no flare – up effect and gonadal function resumes without a lag effect following their discontinuation. Adekunle A.O.
30
GnRH Antagonists (Contd.)
Clinical advantages of GnRH antagonists over GnRH agonists are:
Absence of the initial stimulation of gonadotrophin release (flare-up effect) and
Consequently, a more direct, immediate and reversible suppression of gonadotrophin secretion which allows their use without the need for a densensitization period.
Adekunle A.O.
31
GnRH Antagonists (Contd.) Compared with agonist, it has advantages of:
Short cycle of treatment;
Promise of more conception and less miscarriages;
Reduced amount of GnRH required;
Increase in the incidence of monofollicular ovulation;
Reduction in the incidence of OHSS and multiple pregnancy
Example are Cetrorelix and Ganirelix. Adekunle A.O.
32
ROLE OF PROSTAGLANDINS IN INDUCTION OF LABOUR
There is ample evidence that increase in PGE2 leads to a series of important changes associated with cervical ripening, including:
Dilatation of small vessels in the cervix
Increase in collagen degradation
Increase in hyaluronic acid
Increase in chemotaxis for leukocytes (which causes increased collagen degradation)
Increase in stimulation of Interleukin-8 (IL-8). Adekunle A.O.
33
ROLE OF PROSTAGLANDINS IN INDUCTION OF LABOUR (Contd.)
Prostaglandin F2∝ (PGF2∝) which stimulates an increase in glycosaminoglycans.
Other form of prostagladins is PGE1 (Misoprostol /Cytotec):
Marketed as an anti-ulcer agent;
¼ tablet (25 mcg), which can be crushed and placed on the cervix is effective in inducing cervical ripening and labour.
The application of the medication can be repeated every 4 hours. Adekunle A.O.
34
ROLE OF MISOPROSOL IN PREVENTION OF POSTPARTUM HAEMORRHAGE
600 mcg misoprostol given orally is effective at preventing postpartum haemorrhage;
Misoprostol produces myometrial contractions that induce haemostasis at placental site, thus reducing postpartum bleeding.
Other routes of administration include – sublingual, intravaginal and rectal.
Self-administration of the drug after home birth has been found to lower the incidence of postpartum haemorrhage among women living in rural areas. Adekunle A.O.
35
Mifepristone (RU486) for Inducing Abortion
Mifeprex (RU-486) is a progesterone receptor antagonist.
Has 5 times greater affinity for the receptor than progesterone.
It blocks progesterone, the hormone that maintains pregnancy.
Cervix is softened and dilated.
There is decidual necrosis and detachment of the pregnancy from the endometrium, followed by uterine contractions.
Dose - 600 mg stat orally. Adekunle A.O.
36
MIFEPRISTONE AS EMERGENCY CONTRACEPTION
More effective and fewer side effects than COCs and progestin-only pills;
Significantly less nausea & vomiting than COCs;
High dose — 600 mg Moderate dose — 25 - 50 mg Low-dose — ≤10 mg
Efficacy is not dose-related, but delay in menses is (WHO trial,1999). Adekunle A.O.
37
ANTENATAL CORTICOSTEROIDS
Evidence abounds that a single course of corticosteroids reduces perinatal mortality, respiratory distress syndrome and interventricular haemorrhage.
All pregnant women between 24 and 34 weeks’ gestation who are at risk of pre-term delivery within 7 days should be considered for ante-natal treatment with a single dose of corticosteroids. Adekunle A.O.
38
ANTENATAL CORTICOSTEROIDS (Contd.)
Treatment should consist of: 2 doses of betamethasone given I.M. 24 hours apart, OR 4 doses of dexamethasone given I.M. 12 hours apart
There is no proof of efficacy for any other regimen;
Corticosteroid therapy is contraindicated if a woman suffers from a systemic infection including tuberculosis.
Caution is advised if suspected chorioamnionitis is diagnosed. Adekunle A.O.
39
Management of Hyperprolactenaemia/Galactorrhoea
New non-ergot based dopamine agonists have been developed to replace Bromocriptine in the management of hyperprolactenaemia and galactorrhoea;
Carbagoline Quinagolide
They cause less complications, especially: Headache Postural hypotension Adekunle A.O.
40
CONCLUSION
The last two decades have witnessed several major advances in reproductive endocrinology.
Developments in the field of ART have intensified the hopes and wishes of infertile people to resolve their infertility and have resulted in an increasing demand for such services in both developed and developing countries.
Advances have also occurred in the areas of fertility regulation, induction of labour, management of abortions and Hormone Replacement therapy. Adekunle A.O.
41
1
Advances in Reproductive Endocrinology : Enabling Objectives
Mention the various advances that occurred in Reproductive Endocrinology in the past two decades;
Describe the recent advances in Hormone Replacement Therapy, hormonal contraception and ovulation induction
Comment on the role of steroids in the management of pre-maturity.
List the role of prostaglandins in induction of labour and management of post-partum haemorrhage;
Comment on antiprogestins and abortions. Adekunle A.O.
2
Introduction
Normal reproductive function depends on complex hormonal communication between endocrine and target organs.
Normal function is essential to sexual development at puberty and to the cyclical processes of ovulation and menstruation.
Recent advances in reproductive endocrinology have provided treatment for disease conditions that hitherto could not be managed.
Similarly, these advances have led to introduction of new products for managing gynaecologic and obstetric conditions. Adekunle A.O.
3
Advances in Reproductive Endocrinology
Major advances have occurred in the following areas:
GYNAECOLOGY Hormone Replacement Therapy (HRT) -New routes of administration
Contraception –new, long acting, highly effective methods
Management of infertility – use of GnRH agonists and antagonists in ovulation induction. Adekunle A.O.
4
Recent Advances in Reproductive Endocrinology OBSTETRICS
Prostaglandins Induction of labour Control of post-partum haemorrhage
Antiprogestins In management of abortions
Ante-natal Steroids In the management of pre-term labour Adekunle A.O.
5
Advances in Hormone Replacement Therapy
Oral therapy is the most suitable initial therapy for most women but due to extensive metabolism, only about 10% reach the systemic circulation.
Thus the dose of administered estrogen has to be correspondingly high to achieve effective blood levels.
There is also wide variation in absorption and metabolism during the first pass of intestine/liver.
The so called “first pass” effect has various clinical implications and has led to the introduction of other routes of administration. Adekunle A.O.
6
Transdermal Estrogen
Estrogen has been found to be well absorbed through the skin and subcutaneous fat as well as vaginal epithelium, nasal and sublingual mucosa.
Metabolism in the intestine is avoided.
Pure estradiol can, therefore, be administered directly into the systemic circulation causing a significant rise and an estradiol:estrone ratio similar to that found in premenopausal women Adekunle A.O.
7
ESTRADIOL PATCHES
A patch consists of single transparent matrix with an adhesive layer which contains estradiol.
The dose required is proportionate to the surface area of the patch in contact with the skin.
Cannot be re-applied after being taken off the skin, so it should and need not be taken off prior to bathing.
Changed twice weekly, newer ones last 7 days. Adekunle A.O.
8
ESTRADIOL PATCHES ADVANTAGES
Low dose pure estradiol;
DISADVANTAGES
Local skin reactions; More expensive than tablets;
Avoids intestine and liver metabolism;
Physiological estradiol:estrone ratio;
Not well tolerated in warm climate;
Variable absorption.
Reduces serum triglyceride;
Few side effects. Adekunle A.O.
9
ESTRADIOL GEL
Application of gel containing estradiol;
Hydro-alcoholic gel containing 0.06% w/w 17 β-estradiol ;
Absorption through the skin is rapid while the alcohol evaporates and effective blood levels are obtained;
However, variations in size of the application area may have impact on absorption and the subsequent levels of circulating esradiol;
This route of administration allows the woman a feeling of greater control. Adekunle A.O.
10
ESTRADIOL IMPLANTS
Insertion of pellets of crystalloid estradiol.
Not widely used;
Insertion of the pellets requires a minor surgical procedure –easy, takes only 3 – 4 minutes and is safe.
Pellets of estradiol are available in 25, 50 and 100 mg doses.
The 50 mg dose is most commonly used for HRT and is given at 6 monthly intervals. Adekunle A.O.
11
ESTRADIOL IMPLANTS (Contd.) ADVANTAGES
DISADVANTAGES
Pure estradiol;
Surgical procedure;
Six monthly insertion;
High levels of estradiol in circulation;
Unable to control absorption;
Risk of supraphysiological blood levels;
Difficult to remove pellet; Prolonged release of estradiol
Avoids “first pass” effects; Physiological estradiol:estrone ratio.
Adekunle A.O.
12
ADDITIONAL PROGESTIN
The need to give additional progestin is well established and accepted for women with a uterus;
Until recently, only suitable by the oral route;
Recent advances have produced separate routes.
Adekunle A.O.
13
ROUTES FOR ADDITIONAL PROGESTIN
Progestin can now be incorporated in some matrix patch preparations;
Natural progestin can also be administered via vagina as pessary (avoids first pass hepatic and intestinal metabolism ==> reduced side effects;
Intra-uterine progesterone can be given through an intrauterine device (IUD), e.g., Minera. Adekunle A.O.
14
ADVANCES IN HORMONAL CONTRACEPTION
Major advances have been made in the production of long-lasting and highly effective methods:
Oral Contraceptives
Injectables
Implants
Contraceptive Rings
Emergency Contraceptives Adekunle A.O.
15
ORAL CONTRACEPTIVES
Three new compounds are now widely used:
Combined oral contraceptives containing these progestins have shown almost no adverse changes in:
Norgestimate NG) Gestodene (GD), and Desogestrel (DG).
Carbohydrate and lipid metabolism, Haemostatic system.
They also have less androgenic effects. Adekunle A.O.
16
INJECTABLES
Available formulations (DMPA and NET-EN) are highly effective, long-lasting, safe and reversible.
However, they have high discontinuation rates – menstrual irregularities being the most frequent.
Addition of a short- or medium-acting estrogen into progestin preparations could result in an improvement of endometrial bleeding pattern. Adekunle A.O.
17
NEW INJECTABLES (Contd.)
This has enabled the development of once-amonth injectable contraceptives of:
High efficacy
With bleeding patterns resembling those of the normal menstrual cycle.
The estradiol in these new formulations (cypionate and valerate) are short-acting, yielding elevated serum levels of estradiol for no more than 15 days. Adekunle A.O.
18
NEW INJECTABLES (Contd.) CYCLOFEM
Contains low doses of medroxyprogesterone acetate (25 mg) and estradiol cypionate (5 mg).
MESYGINA
Contains low doses of NET-EN (50 mg) and estradiol valerate (5 mg).
Both preparations have proved their high efficacy in large multicentre studies. Adekunle A.O.
19
IMPLANTS
The observation that steroid hormones can be released at a constant rate from silicone rubber for long periods of time led to the development of subdermal implants for contraception in humans.
The last two decades have witnessed great strides in the development of several types of subdermal implant systems.
Basically, two groups have emerged: Biodegradable Implants Non-biodegradable Implants Adekunle A.O.
20
NEW IMPLANTS JADELLE
2-implant system, designed to release the same amount of levonorgestrel as Norplant;
Accomplished through a modification in the design of the implant, which consists of an inner rod containing a mixture of 50% levonorgestrel and 50% silastic membrane. IMPLANON (Organon)
Single implant containing 3-keto-desogestrel, the major metabolite of progestin desogestrel. Adekunle A.O.
21
NEW IMPLANTS (Contd.) ST 1435 (NESTERONE) IMPLANT
Single implant system that releases the synthetic progestin ST 1435 (16-methylene-17acetoxy-19 norprogesterone);
Designed for two years;
Not biologically active when taken orally, thus permits the use of implant in nursing mothers. ANNUELLE (NET Implant)
Consists of 4 – 5 small pellets made of 90% norethidrone (NET) and 10% cholesterol.
Effective for 1 year, Non-biodegradable. Adekunle A.O.
22
Levonorgestrel Intrauterine System (MirenaTM)
A T-shaped polyethylene device.
The frame is 32 millimeter in both the horizontal and the vertical directions.
The cylindrical reservoir around the vertical stem contains a mixture of silicone and 52 mg of levonorgestrel, a progestin widely used in implants, oral contraceptives, and vaginal rings.
25 microgram of levonorgestrel is released every day.
A monofilament removal thread is attached to a loop at the end of the vertical stem. Adekunle A.O.
23
Levonorgestrel Intrauterine System TM (Mirena )
Mirena has many advantages over the copper IUDs.
It is highly effective with the first year failure rate of 0.1 percent and five year cumulative failure rate of 0.7 percent.
There is a marked reduction in menstrual blood loss and the systemic level of hormone is very low as compared to the other progesterone-only methods.
Unlike copper IUDs, Mirena provides dramatic relief in dysmenorrhea Adekunle A.O.
24
Levonorgestrel Intrauterine System TM (Mirena )
Once inserted it is effective for 5 years and fertility returns rapidly on discontinuation. Eighty percent of the women intending to get pregnant will become pregnant within 12 months of discontinuing Mirena.
Mirena has many non-contraceptive benefits:
It has beneficial effect on menorrhagia and dysmenorrhea, Reduces the risk of pelvic inflammatory disease, It also reduces the risk of endometrial cancer by 50% Adekunle A.O.
25
CONTRACEPTIVE VAGINAL RINGS
Hormones diffuse continuously from a reservoir within a ring inserted into the vagina.
Convenient, does not require daily administration or attention;
Entirely under the control of the client;
Steady blood levels of steroids allows a greater contraceptive effect from a low-dose steroid.
Rings come both as combined formulations – containing progestin and estrogen - and as progestin-only formulations. Adekunle A.O.
26
MALE HORMONAL CONTRACEPTION
Testosterone or a combination of testosterone and progestin is used to suppress sperm production;
When testosterone is administered, the levels are lowered in the testes, resulting in reduced sperm production.
Pills, patches, injections, and implants have been tested to deliver various formulations of testosterone.
Injected formulations appear to be the most effective in suppressing sperm production. Adekunle A.O.
27
ADVANCES IN OVULATION INDUCTION
A better understanding of the hormonal control of human folliculogenesis has allowed physicians to use ovarian stimulation in every clinical situation where the main goal is to achieve pregnancy.
Controlled ovarian stimulation (COH) has increasingly become a new tool in many situations.
These include the use of GnRH Analogues – peptides in which the primary structure of GnRH has been altered by the deletion or substitution of one or more amino acids. Adekunle A.O.
28
GnRH Agonists (GnRH-a)
Ability of GnRH agonists to suppress LH concentration before and during ovarian stimulation has earned them an undisputed place in IVF treatment protocols. FORMULATIONS AVAILABLE
Buserelin, Leuprolide, Goserelin, Histrelin, Triptorelin; single dose subcut.
Buserelin, Nafarelin 2-4 times daily as nasal spray. Absoption into systemic circulation is poor.
Leuprolide, Triptorelin I.M. monthly as depot preparation (endometriosis and fibroids) Adekunle A.O.
29
GnRH Antagonists
GnRH antagonists are synthetic analogues of GnRH that compete with endogenous GnRH for pituitary binding sites but are unable to induce GnRH receptor cross-linking;
This process appears to be necessary to effect calcium ion-mediated gonadotrophin release.
Antagonists suppress GnRH release within a few hours, have no flare – up effect and gonadal function resumes without a lag effect following their discontinuation. Adekunle A.O.
30
GnRH Antagonists (Contd.)
Clinical advantages of GnRH antagonists over GnRH agonists are:
Absence of the initial stimulation of gonadotrophin release (flare-up effect) and
Consequently, a more direct, immediate and reversible suppression of gonadotrophin secretion which allows their use without the need for a densensitization period.
Adekunle A.O.
31
GnRH Antagonists (Contd.) Compared with agonist, it has advantages of:
Short cycle of treatment;
Promise of more conception and less miscarriages;
Reduced amount of GnRH required;
Increase in the incidence of monofollicular ovulation;
Reduction in the incidence of OHSS and multiple pregnancy
Example are Cetrorelix and Ganirelix. Adekunle A.O.
32
ROLE OF PROSTAGLANDINS IN INDUCTION OF LABOUR
There is ample evidence that increase in PGE2 leads to a series of important changes associated with cervical ripening, including:
Dilatation of small vessels in the cervix
Increase in collagen degradation
Increase in hyaluronic acid
Increase in chemotaxis for leukocytes (which causes increased collagen degradation)
Increase in stimulation of Interleukin-8 (IL-8). Adekunle A.O.
33
ROLE OF PROSTAGLANDINS IN INDUCTION OF LABOUR (Contd.)
Prostaglandin F2∝ (PGF2∝) which stimulates an increase in glycosaminoglycans.
Other form of prostagladins is PGE1 (Misoprostol /Cytotec):
Marketed as an anti-ulcer agent;
¼ tablet (25 mcg), which can be crushed and placed on the cervix is effective in inducing cervical ripening and labour.
The application of the medication can be repeated every 4 hours. Adekunle A.O.
34
ROLE OF MISOPROSOL IN PREVENTION OF POSTPARTUM HAEMORRHAGE
600 mcg misoprostol given orally is effective at preventing postpartum haemorrhage;
Misoprostol produces myometrial contractions that induce haemostasis at placental site, thus reducing postpartum bleeding.
Other routes of administration include – sublingual, intravaginal and rectal.
Self-administration of the drug after home birth has been found to lower the incidence of postpartum haemorrhage among women living in rural areas. Adekunle A.O.
35
Mifepristone (RU486) for Inducing Abortion
Mifeprex (RU-486) is a progesterone receptor antagonist.
Has 5 times greater affinity for the receptor than progesterone.
It blocks progesterone, the hormone that maintains pregnancy.
Cervix is softened and dilated.
There is decidual necrosis and detachment of the pregnancy from the endometrium, followed by uterine contractions.
Dose - 600 mg stat orally. Adekunle A.O.
36
MIFEPRISTONE AS EMERGENCY CONTRACEPTION
More effective and fewer side effects than COCs and progestin-only pills;
Significantly less nausea & vomiting than COCs;
High dose — 600 mg Moderate dose — 25 - 50 mg Low-dose — ≤10 mg
Efficacy is not dose-related, but delay in menses is (WHO trial,1999). Adekunle A.O.
37
ANTENATAL CORTICOSTEROIDS
Evidence abounds that a single course of corticosteroids reduces perinatal mortality, respiratory distress syndrome and interventricular haemorrhage.
All pregnant women between 24 and 34 weeks’ gestation who are at risk of pre-term delivery within 7 days should be considered for ante-natal treatment with a single dose of corticosteroids. Adekunle A.O.
38
ANTENATAL CORTICOSTEROIDS (Contd.)
Treatment should consist of: 2 doses of betamethasone given I.M. 24 hours apart, OR 4 doses of dexamethasone given I.M. 12 hours apart
There is no proof of efficacy for any other regimen;
Corticosteroid therapy is contraindicated if a woman suffers from a systemic infection including tuberculosis.
Caution is advised if suspected chorioamnionitis is diagnosed. Adekunle A.O.
39
Management of Hyperprolactenaemia/Galactorrhoea
New non-ergot based dopamine agonists have been developed to replace Bromocriptine in the management of hyperprolactenaemia and galactorrhoea;
Carbagoline Quinagolide
They cause less complications, especially: Headache Postural hypotension Adekunle A.O.
40
CONCLUSION
The last two decades have witnessed several major advances in reproductive endocrinology.
Developments in the field of ART have intensified the hopes and wishes of infertile people to resolve their infertility and have resulted in an increasing demand for such services in both developed and developing countries.
Advances have also occurred in the areas of fertility regulation, induction of labour, management of abortions and Hormone Replacement therapy. Adekunle A.O.
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