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2 REPRODUCTIVE ENDOCRINOLOGY ---Provides comprehensive care for a wide range of reproductive problems. ---Common problems evaluated and treated include:-  Infertility (primary and secondary)  Pregnancy loss  General female hormonal disorders  Hirsutism (excessive hair growth)  Menopausal symptoms  Endometriosis

3 REPRODUCTIVE ENDOCRINOLOGY  Menstrual disorders/problems  Osteoporosis  Pelvic pain  Polycystic Ovarian Syndrome (PCOS)  Premenstrual Syndrome  Uterine abnormalities  Sexual dysfunction

4 WHO IS A REPRODUCTIVE ENDOCRINOLOGIST?  A reproductive endocrinologist is a sub specialist physician who has received training (a residency) in Obstetrics and Gynaecology, and advanced training (a fellowship) in the treatment of INFERTILITY, RECURRENT MISCARRIAGES and HORMONAL DISORDERS in women.

5 WHAT TREATMENT DO REPRODUCTIVE ENDOCRINOLOGISTS OFFER?  Reproductive endocrinologist can perform a wide variety of treatments for infertility.  A variety of fertility tests are run in order to determine the cause of infertility.  Reproductive endocrinologists are trained in advanced procedures that can increase a couples chances of conceiving such as:  ---Infertility Surgeries,  ---Procedures to reverse tubal ligation,  ---Use of fertility drugs (e.g. Clomid,Pergonal, Follistim, Repronox) and  ---Assisted Reproductive Techniques (ART).

6 ADVANCES IN REPRODUCTIVE ENDOCRINOLOGY  Assisted Reproductive Techniques (ART).  Minimal invasive surgeries.  Cloning.  Embryonic stem cells.

7 A) ASSISTED REPRODUCTIVE TECHNIQUES (ART)  Any procedure where the gamete is manipulated or removed from the body and returned either as an oocyte or as an embryo.  The aim is to approximate the eggs and sperms at the same time whether within or outside the body.

8 A) ASSISTED REPRODUCTIVE TECHNIQUES (ART)(CONTD)  Reproductive technologies have undergone a rapid evolution from simple procedures like the first insemination of fresh donor semen almost half a century ago to a position where we now have the ability to collect epididymal sperm for micro injection into oocytes; freeze, thaw, and transfer donor gametes and embryos, create pregnancies in menopausal women, and in the near future may be able to harvest and store eggs from ovarian biopsies.

9 INDICATIONS FOR ART  ART is indicated for the management of infertility for which conventional care is INAPPROPRIATE or has FAILED.  These include: ---Tubal damage ---Tubal damage ---Oligospermia --- < 20 million sperms/ml. ---Oligospermia --- < 20 million sperms/ml. ---Azoospermia ---Azoospermia ---Unexplained infertility ---Unexplained infertility

10 INDICATIONS FOR ART(CONTD) ***Most recently, ART has made possible the  Preimplantation diagnosis of genetic disease.  Removal and subsequent chromosomal analysis of a single blastomere allows, prior to implantation, for the diagnosis of certain disorders e.g. Homozygous sickle cell disease and Duchene muscular dystrophy. *** It is appropriate that ART is increasingly attracting the attention of doctors,nurses, scientists and the general public,but it must be realized that high-tech ART are only necessary when other simpler and cheaper measures have been tried without success. *** It is therefore necessary to fully investigate both the male and female partners and to take into account all available options.

11 FACTS ABOUT INFERTILITY  Accounts for 50% of cases in the gynaecological clinics in developing countries.  Numbers of consultations have risen significantly.  It affects 1 in 10 couples.

12 DEFINITIONS IN INFERTILITY  INFERTILITY – Inability of a couple to achieve pregnancy (conception) after 12 months (1 year) of unprotected regular sexual intercourse (Involuntary failure to conceive).  There are 2 types of Infertility:  PRIMARY INFERTILITY - No previous pregnancy.  SECONDARY INFERTILITY- Previous pregnancy (irrespective of the outcome).

13 DEFINITIONS IN INFERTILITY(CONTD)  INFECUNDABILITY- Inability of a couple to achieve a live birth after 12 months of regular unprotected intercourse.  VOLUNTARY INFERTILITY- has never tried for a pregnancy and has taken contraception to avoid pregnancy.  FERCUNDITY- is the capacity to participate in the production of a child.  FECUNDABILITY- is the likelihood of pregnancy per month of exposure.

14 DEFINITIONS IN INFERTILITY(CONTD)  STERILITY- An intrinsic inability to achieve pregnancy. (Total inability to get pregnant). (Infertility is Relative).  CHILDLESSNESS- No child at the end of reproductive life.  * The chances of conception should be expressed in terms of fertility of the couple rather than the individual partner.  * Infertility is associated with emotional and social distress.  * The longer the couple have been trying to conceive without success, the greater the decline in conception rate.

15 CONTRIBUTION OF THE PARTNERS TO INFERTILITY  Male % - 40%  Female % - 40%  Both %  Unexplained % -10%

16 CHANCES OF PREGNANCY  60% of couples conceive months.  80%-85% conceive yr.  90% conceive ----2yrs  10-15% ----Infertile

17 WHAT IS THE MAGNITUDE OF INFERTILITY IN NIGERIA  It is estimated that 15-20% of couples are facing this problem at any given time.  In Nigeria, this translates to 2 million couples (i.e. 4 million individuals) that are experiencing infertility at any given time.

18 PROBLEMS OF INFERTILITY IN OUR ENVIROMENT  Social Stigma.  Marital instability and social neglect.  Exploitation and economic deprivation of female partners.  Emotional stress / frustration / strained relationships/ guilt feelings/ unhappiness and unfulfilled lives / Psychological consequences.  Male ego.  Divorce.

19 FACTORS CONTRIBUTING TO THE INCREASED DEMAND OF TREATMENT  Increased numbers of women in the reproductive age group.  A trend towards a later age of child bearing, with more years of exposure to infections or toxins as well as age- specific reduction in fertility.  Greater public awareness of the availability and scope of such services.  Availability of new technology and drugs for treatment of previously hopeless cases.

20 COMMON CAUSES OF INFERTILITY IN OUR ENVIRONMENT  * Male Infertility Infections Gonococcal Chlamydia Chlamydia  * Female Infertility Tubo – Peritoneal factors (Bilateral blockage/pelvic- (Bilateral blockage/pelvic- adhesions are the commonest) adhesions are the commonest) S T I S T I Post abortal sepsis Post abortal sepsis Puerperal sepsis Puerperal sepsis

21 WHEN TO INVESTIGATE INFERTILE COUPLES  When conception does not occur within 1 year of unprotected regular coitus.  This period could be shortened in certain individuals.  It is good to complete investigations within 1 menstrual cycle at least the initial evaluation.

22 PRINCIPLES OF MANAGEMENT  Deal with the infertile couple together.  No one is ‘at fault’ or ‘to blame’  Carry out investigations and treatment consistently in proper sequence.

23 HISTORICAL DEVELOPMNTS OF ART  1970s -----Experiments in ovum retrieval IVF + ET.  st IVF – ET baby born at Oldham,Manchester,U.K---- Steptoe and Oldham,Manchester,U.K---- Steptoe and Edwards who were the IVF pioneers. Edwards who were the IVF pioneers. (Louise Brown born on 25th July, 1978 and is (Louise Brown born on 25th July, 1978 and is presently expecting her first baby which was presently expecting her first baby which was conceived by natural means). conceived by natural means). (The Worlds first “Test tube baby”). (The Worlds first “Test tube baby”).  st Successful human pregnancy following cryopreservation. cryopreservation.  st live birth via GIFT.

24 HISTORICAL DEVELOPMNTS OF ART(CONTD)  st live birth via GIFT.  st human pregnancy via PZD.  st pregnancy via SUZI.  st pregnancy and birth following ICSI. ICSI.  1997 till date ----Experimentation and reports on mammalian and human cloning.  1997 till date ----Stem cell research.

25 TYPES OF ASSISTED REPRODUCTIVE TECHNIQUES  Many procedures and many acronyms which are rapidly changing.  Variations of the same standard techniques. 1). Timed Intercourse (T.I.) 2). Intra-Uterine Insemination (IUI) 3). In - Vitro Fertilization and Embryo Transfer (IVF - ET) 4). Gamete Intra Fallopian Transfer (GIFT) 5). Zygote Intra Fallopian Transfer (ZIFT) 6).Subzonal Insemination (SUZI)

26 TYPES OF ASSISTED REPRODUCTIVE TECHNIQUES(CONTD) 7). Intra Cytoplasmic Sperm Injection (ICSI) 8). Direct Oocyte Sperm Transfer (DOST) 9). Sperm Aspiration Techniques.  TESA --- Testicular Sperm Aspiration  PESA --- Percutaneous Sperm Aspiration  MESA --- Micro Epididymal Sperm Aspirations. 10). Embryo Freezing. 11).Third Party ART(Donor Eggs, Donor Sperms or Surrogacy).

27 SOME ART PROCEDURES 1).TIMED INTERCOURSE  Medications are administered to promote ovulation.  Treatment monitored by ultrasound scanning to determine the precise timing of the egg release.  The couples are then advised on the best timing of intercourse.

28 ART PROCEDURES (CONTD) 2). INTRA UTERINE INSEMINATION  Treatment and monitoring is like in timed intercourse.  The sperms are specially prepared and introduced into the uterine cavity via a catheter.  This can help to overcome cervical mucus hostility.

29 ART PROCEDURES (CONTD) 3).IN-VITRO FERTILIZATION AND EMBRYO TRANSFER (IVF- ET) A)---- Unlike the standard ovulation induction regimes, most IVF programs follow the super ovulation regime as this ensures a greater number of harvestable eggs This consists of an initial pituitary down regulation (desensitization of the pituitary) with a resultant complete suppression of ovarian activity This consists of an initial pituitary down regulation (desensitization of the pituitary) with a resultant complete suppression of ovarian activity.  Drugs used include the subcutaneous or intranasal GnRH(Gonadotrophin-releasing hormone) analogues(Buserelin,Naferelin,Triptorelin) from Day 1 to 14 of the menstrual cycle. 1 to 14 of the menstrual cycle.

30 ART PROCEDURES (CONTD)  This is followed by the standard Human chorionic gonadotrophin (FSH, LH) and Human menopausal gonadotrophin regime (LH). B) -----HCG is given when there are at least 3 follicles mm in diameter. C) -----Laparoscopic or preferably transvaginal ultrasound guided follicular aspiration approximately 36 hours after HCG injection. D) -----Incubation of aspirated eggs (under strict temperature, gas and aseptic control) for 4-6hrs.This allows development to stage two metaphase. This is followed by addition of about 200,000 capacitated sperms per egg.

31 ART PROCEDURES (CONTD) E) Regular stereoscopic microscopic evaluation is done to determine progress of fertilization etc F) Usually after hrs, the resultant embryos (2- 8 cell stage) are aspirated into a small catheter and transcervically placed in the uterine cavity. Usually two are placed while the remaining may be cryopreserved for future use or donated. G) ----Luteal support is provided by the administration of low dose hCG or progesterone.

32 ART PROCEDURES (CONTD) IVF RESULTS  The realistic pregnancy rate per ET in IVF is 20-30% overall but this is influenced by age and the number of embryos transferred.  Younger women < 35 years have at least a 33% success rate.

33 ART PROCEDURES (CONTD) COMPLICATIONS OF IVF i) Multiple pregnancies  1 in 5 IVF pregnancies are multiple if transferring 3 embryos or less.  Transferring more than 3 embryos(where available) results in multiple pregnancies in about 40% of IVF babies.

34 ART PROCEDURES (CONTD) ii) Ovarian hyperstimulation syndrome(OHSS)  Excess response to ovarian stimulants can lead to ovarian enlargement, abdominal distension and pains in up to 7% of IVF patients.  However, serious OHSS involving gross ascites affects less than 2% of all patients.  The prevention of OHSS is the identification of women at risk (polycystic ovaries, high responders) and either reduced hMG doses or electively cryopreserving all embryos to avoid pregnancy until the danger has been averted.

35 ART PROCEDURES (CONTD) iii) Pelvic infection  Serious infection is rare in IVF.  Prophylactic antibiotics are advised. iv) Haemorrhage  This can occur during egg collection.  Usually there is a bleeding point, but this stops when pressure is applied for a short while.

36 ART PROCEDURES (CONTD) v) Ectopic pregnancy vi) Anembryonic pregnancy (Blighted ovum) vii) Spontaneous abortion viii) Intrauterine growth restriction (IUGR) ix) Preterm delivery

37 ART PROCEDURES (CONTD) 4).GAMETE INTRAFALLOPIAN TRANSFER (GIFT)  Indicated in patients with at least one normal tube.  Super ovulation is as above (in IVF-ET) followed by a laparoscopic follicular aspiration.  Capacitated sperms and eggs are mixed and placed in the catheter.  Both are then transferred into the fallopian tubes.  In this case fertilization occurs naturally within the body.  GIFT is not recommended if the fallopian tubes are blocked or the sperm quality is far below average.

38 ART PROCEDURES (CONTD) 5). ZYGOTE INTRA FALLOPAIN TRANSFER (ZIFT)  Similar to GIFT except that the sperms and eggs are incubated first and transferred after fertilization.

39 ART PROCEDURES (CONTD) 6). INTRA CYTOPLASMIC SPERM INJECTION (ICSI) ***Indicated in patients with;  i) Severe oligospermia < 5million/ml,  ii) Significant sperm immotility,  iii) Multiple sperm factors,  iv) Failed IVF – ET or  v) Inability of the sperms to penetrate the egg as confirmed from the ZONA PELUCIDA PENETRATION TEST.

40 ART PROCEDURES (CONTD)  Steps involved are similar to IVF – ET except that after aspiration of the eggs, (under an inverted microscope) the eggs and sperm are held by a system of two hyallically - controlled micropipettes.  An egg is held in place by a micropipette while another micropipette picks up a single live sperm. The egg cell membrane is then pierced and the sperm injected into the cytoplasm with the resultant fertilization of the egg.

41 ART PROCEDURES (CONTD) 7).SPERM ASPIRTION PROCEDURES  Indicated in severe oligospermia. This may consist of:  I) Testicular Sperm Aspiration (TESA)  II) Percutaneous Sperm Aspiration (PESA),  III) Micro Epididymal Sperm Aspiration (MESA).

42 ART PROCEDURES (CONTD) 8).THIRD PARTY ART I) Donor Sperms  Absence of sperms in the man especially due to testicular failure has traditionally been treated with donor sperms for several decades.  In these days, it is possible to extract directly from the testes in obstructive azoospermia and the sperms directly injected into the eggs.  Where this procedure of sperm extraction (PESA/TESA) fails, the only recourse is to use donor sperms if the couple desires a pregnancy.

43 ART PROCEDURES (CONTD) II) Donor eggs  In menopausal or perimenopausal women desiring pregnancy, eggs can be obtained from willing donors (that may be known or unknown to the recipient), fertilized with the husbands sperms and the embryos transferred into the uterus of the older woman. III) Surrogacy  Couples desiring their own genetic children, but where the woman has had a hysterectomy or severe damage to her uterus or endometrium, can opt for the use of a surrogate mother’s uterus to receive embryos generated from the eggs and sperms of the genetic parents.

44 PRE – CONCEPTION DIAGNOSIS  SEX SELECTION --- Sex-gene probes have been available for several years for embryo sexing, especially where there are concerns about sex linked diseases. Social sex selection has ethical implications.  SICKLE CELL DISEASE PREVENTION --- Embryos selection based on the absence of genetic diseases (sickle cell disease is the most common in our environment) is more acceptable in most cultures or religions than selective pregnancy termination after antenatal diagnosis.  Pre-conception diagnosis can be applied to just about any chromosomal disease, sex-linked disorders or inborn errors of metabolism for which appropriate probes have been developed.

45 ISSUES IN ASSISTED REPRODUCTION  Cost effectiveness  Ethical / moral / legal considerations  Emotional issues

46 B)MINIMALLY INVASIVE SURGICAL OPTIONS IN REPRODUCTIVE ENDOCRINOLGY  Developments of new surgical techniques and advances in surgical equipments allow us to perform more and more surgical procedures using LAPAROSCOPY and HYSTEROSCOPY.  These novel procedures have revolutionized the approach to the majority of gynecological disorders.  We can now perform the majority of surgeries without the need for larger incisions in the abdominal wall and therefore, most often patients can go home on the day of surgery and recover to full activity in approximately two weeks after surgery.

47 MINIMALLY INVASIVE SURGICAL OPTIONS IN REPRODUCTIVE ENDOCRINOLGY(CONTD) 1) LAPAROSCOPY  This refers to the transabdominal visualization of the peritoneal cavity usually after insuflation with gas.  Indications for laparoscopy could be diagnostic or therapeutic.

48 MINIMALLY INVASIVE SURGICAL OPTIONS IN REPRODUCTIVE ENDOCRINOLGY(CONTD) Diagnostic Indications for Laparoscopy Include the evaluation of amongst others:  Chronic and acute pelvic pain of indeterminate origin e.g. endometriosis, acute PID, leaking ectopic gestation, ovarian cysts/accidents  Causes of infertily  Second look evaluation following treatment for cancer of the ovary  Suspected endometriosis  Uterine perforation  Follicular growth monitoring

49 MINIMALLY INVASIVE SURGICAL OPTIONS IN REPRODUCTIVE ENDOCRINOLGY(CONTD) Therapeutic Indications for Laparoscopy Include:  Tubal sterilization either by electrical or insertion of bands, rings etc  Pelvic adhesiolysis  Retrieval of lost IUCDs  Aspiration of ovarian cysts including ovarian cystectomy, wedge resection of the ovary and ovarian biopsy.  Laparoscopic myomectomy

50 MINIMALLY INVASIVE SURGICAL OPTIONS IN REPRODUCTIVE ENDOCRINOLGY(CONTD)  Metroplasty  Laparoscopic assisted vaginal hysterectomy,LAVH  Laparoscopic tubal surgery, which may include salpingectomy, salpingostomy, tubal re- implantation  Laparoscopic lymphadenectomy, colposuspension  As part of the assisted fertilization procedures – ova collection, gamete transfer

51 MINIMALLY INVASIVE SURGICAL OPTIONS IN REPRODUCTIVE ENDOCRINOLGY(CONTD) 2) HYSTEROSCOPY  Is the endoscopic evaluation of the uterine cavity using the Hysteroscope.  The Hysteroscope is very much like an operating Laparoscope with an added channel for the introduction of fluids used for the distension of the uterine cavity.  Distending media include high molecular weight dextran with normal saline,glycine, and 5% dextrose in water or carbon dioxide.

52 MINIMALLY INVASIVE SURGICAL OPTIONS IN REPRODUCTIVE ENDOCRINOLGY(CONTD)  With the use of the liquid media, the uterine pressure should not exceed 150mmHg, and with the use of Co2 the flow rate should also not exceed 100ml/mixture.  Hysterosopic evaluations may be performed either under local or general aneasthesia. aneasthesia.

53 MINIMALLY INVASIVE SURGICAL OPTIONS IN REPRODUCTIVE ENDOCRINOLGY(CONTD) Diagnostic and therapeutic indications for HysteroscopyInclude:  Focal biopsy for evaluation of patients with abnormal uterine bleeding.  Evaluation of patients with infertility  Hysteroscopic endometrial laser coagulation instead of hysterectomy in patients with endometrial hyperplasia or dysfunctional uterine bleeding  Hysteroscopic submucous myomectomy or metroplasty  Diagnosis and management of Asherman’s syndrome

54 MINIMALLY INVASIVE SURGICAL OPTIONS IN REPRODUCTIVE ENDOCRINOLGY(CONTD)  Identification and retrieval of lost IUCDs  Excision of polyps  Sterilization

55 C)CLONING  The first mammal cloned from the cell of an adult, DOLLY THE SHEEP, generated considerable interest worldwide. generated considerable interest worldwide.  It stimulated much discussion about the ethics of cloning and also, in particular, the potential for human reproductive cloning.

56 CLONING(CONTD)  Dolly was derived from the udder ( an organ shaped like a bag that produces milk and hangs beneath the body) of a six- year old FINN DORSET EWE that was cultured in the laboratory. The cultured cells were then fused with unfertilized eggs, from which the nuclei had been removed. The variable reconstituted eggs were then implanted into the SURROGATE BLACK EWE. One implanted egg resulted in the birth of DOLLY. **** An ewe is a female sheep. **** An ewe is a female sheep.

57 CLONING(CONTD)  The production of DOLLY demonstrated for the first time that a NUCLEUS taken from an adult cell could be REPROGRAMMED to permit the full range of GENE EXPRESSIONS needed to produce a COMPLETE ANIMAL.  A clear distinction should be drawn between ‘REPRODUCTIVE CLONING’ and ‘THERAPEUTIC’ (NON – REPRODUCTIVE) CLONING.

58 CLONING(CONTD)  REPRODUCTIVE CLONING --- by either embryo splitting or nucleus replacement, is aimed at birth of genetically identical individuals. ****There are no ethical objections to ****There are no ethical objections to genetically identical individuals per se, genetically identical individuals per se, but there are serious ethical questions but there are serious ethical questions about instrumentation of human beings. about instrumentation of human beings.

59 CLONING(CONTD)  THERAPEUTIC (NON- REPRODUCTIVE) CLONING --- is a term used to describe the use of cloning that does not involve the production of genetically identical individuals, has SCIENTIFIC and THERAPEUTIC applications including potential therapy for mitochondrial disease and research on EMBRYONIC STEM CELLS, which could lead to the development of tissue and possibly organs without the risk of immune rejection.

60 CLONING(CONTD) ****Such cell-based therapies might be used to treat Parkinson’s and Huntington’s disease (nerve cells), muscular dystrophy (striated muscle cells) and leukaemia(white blood cells).

61 D) EMBYONIC STEM CELLS  Researchers have been making embryonic stem cells from mice, hamsters and other animals for several years.  They have been described as the ultimate spare part.  Embryonic stem cells are found in early stages of the embryo, after the egg is fertilized and has begun dividing, but before the mass of cells attach itself to the wall of the uterus.  Eventually they differentiate into the various cell types in the body, and disappear.

62 EMBYONIC STEM CELLS(CONTD)  Researchers have been able to capture these cells in their undifferentiated state and keep them in that state in a culture.  They are presently working on how to direct these cells to become specific types of cells which would allow scientists to grow an unlimited supply of cells for transplant and other aspects of medicine and biology.

63 EMBYONIC STEM CELLS(CONTD)  Much of the excitement surrounding embryonic stem cell research focuses on their potential for transplantation to repair diseased organs.  With their unique ability to differentiate into all cells of the body, stem cells may be used to treat a variety of disorders, ranging from diabetes to Parkinson’s disease and spinal cord injuries.

64 CONCLUSION  The introduction of these advances has provided not only hope and treatment for the infertile couple but also stimulated continuing research in the field of reproduction.  Reproductive advances will make more COUPLES happier.




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