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Anovulation: Aetiology and Management Dr. Darron Halliday Outline Introduction Causes suitable for ovulation induction Causes unsuitable for ovulation induction Drug induced Diagnosis of anovulatory subfertility Management of anovulation Anovulation :Aetiology and Management Introduction Disorders of ovulation account for about 20% -30% of infertility and often present with oligomenorrhoea or amenorrhoea The majority fall into the WHO group II category Many of the treatments are simple and effective Anovulation can sometimes be treated with medical or surgical induction Anovulation :Aetiology and Management ACOG 2002, Fairley and Taylor BMJ 2003 Anovulation :Aetiology and Management Anovulation :Aetiology and Management Causes of anovulation suitable for ovulation induction treatment Hypothalamic Low concentration of gonadotrophin realeasing hormone (hypogonadotrophic hypogonadism) Weight or exercise related amenorrhoea Kallman's syndrome Stress Idiopathic Anovulation :Aetiology and Management Causes of anovulation suitable for ovulation induction treatment Pituitary • Hyperprolactinaemia • Pituitary failure (hypogonadotrophic hypogonadism) • Sheehan's syndrome • Craniopharyngioma or hypophysectomy • Cerebral radiotherapy Anovulation :Aetiology and Management Causes of anovulation suitable for ovulation induction treatment Ovarian • Polycystic ovaries Other endocrine • Hypothyroidism • Congenital adrenal hyperplasia Anovulation :Aetiology and Management Causes suitable for ovulation induction Hypogonadotrophic hypogonadism is characterised by a selective failure of the pituitary gland to produce luteinising hormone and follicle stimulating hormone BMI < 20 Kg/m2 gymnasts, marathon runners, ballerinas—may develop amenorrhoea because of a physiological reduction in the hypothalamic production of gonadotrophin releasing hormone Anovulation :Aetiology and Management Weight-related amenorrhoea Anorexia Nervosa Abnormal body image, intense fear of weight gain, often strenuous exercise Mean age onset 13-14 yrs (range 10-21 yrs) Low estradiol risk of osteoporosis Bulemics less commonly have amenorrhea due to fluctuations in body wt, but any disordered eating pattern (crash diets) can cause menstrual irregularity. Treatment : body wt. (Psychiatrist referral) Anovulation :Aetiology and Management Causes suitable for ovulation induction Sheehan's syndrome - caused by infarction of the anterior pituitary venous complex (usually after massive postpartum haemorrhage or trauma) Kallman's syndrome- (amenorrhoea with anosmia caused by congenital lack of hypothalamic production of gonadotrophin releasing hormone). Anovulation :Aetiology and Management cerebral irradiation RX for craniopharyngioma or some forms of leukaemia may affect the hypothalamus or the pituitary may resulting in hypogonadotrophic hypogonadism Anovulation :Aetiology and Management Hyperprolactinaemia caused by a pituitary microadenoma. causes reduction in the production of pituitary luteinising hormone and follicle stimulating hormone. Causes secondary amenorrhoea, galactorrhoea, headaches or disturbed vision treatment with drugs result in subsequent resumption of menses and fertility Anovulation :Aetiology and Management Polycystic ovary syndrome The most common cause of chronic anovulation (70%) Hyperandrogenism ; LH/FSH ratio Insulin resitance is a major biochemical feature ( blood insulin level hyperandrogenism ) Long term risks: Obesity, hirsutism, infertility, type 2 diabetes, dyslipidemia, cardiovasular risks, endometrial hyperplassia and cancer Treatment depends on the needs of the patient and preventing long term health problems Anovulation :Aetiology and Management Transvaginal scan of a polycystic ovary. Typically 10 or more follicles of <10 mm in diameter ("string of pearls") are in a single transverse or longitudinal section through the ovary. Stromal density and ovarian volume increase Anovulation :Aetiology and Management Psychogenic Hypothalamic Amenorrhea Amenorrhea and anovulation a definite history of psychological and socioenvironmental trauma Characterized by low to normal basal levels of serum gonadotropins with normal responses to GnRH, prolonged suppression of gonadotropins in response to estradiol, and failure of a positive feedback response to estradiol, increased basal levels of cortisol and decreased levels of DHEAS Anovulation :Aetiology and Management Psychogenic Hypothalamic Amenorrhea The mechanism by which emotional states or stressful experiences cause psychogenic amenorrhea is not yet established. Higher centers have copious connections with the hypothalamus Evidence suggests that a cascade of neuroendocrine events that may begin with limbic system responses to psychic stimuli impairs hypothalamic-pituitary activity It has been suggested that increased hypothalamic b-endorphin is important in inhibiting gonadotropin secretion Anovulation :Aetiology and Management Psychogenic Hypothalamic Amenorrhea Associated factors a history of previous pregnancy losses stressful life events within the 6-month period preceding the amenorrhea poor social support or separation psychosexual problems and socioenvironmental stresses during the teenage years have negative attitudes toward sexually related body parts, more partner-related sexual problems, and greater fear of or aversion to menstruation than do eumenorrheic women Anovulation :Aetiology and Management Psychogenic Hypothalamic Amenorrhea Treatment. The treatment of patients with stress induced hypothalamic chronic anovulation is controversial. Psychological therapy and support or a change in lifestyle may cause cyclic ovulation and menses to resume Ovulation induction - as will be discussed Anovulation :Aetiology and Management Causes unsuitable for ovulation induction Ovarian failure • Idiopathic • Radiotherapy or chemotherapy • Surgical removal • Genetic • Autoimmune Chromosomal • Turner's syndrome (45,X) • Androgen insensitivity syndrome (46,XY) Anovulation :Aetiology and Management Premature Ovarian Failure Ovarian failure before the age of 40 yrs is POF, absence of menses for 3 cycles/6mths Unfortunately this is an irreversible condition. The only treatment option that can result in conception is the use of donated eggs with in vitro fertilisation Estrogen most effective rx for hot flashes, vag dryness, urinary s/s, emotional lability (6m-5yrs), long term: CHD, osteoporosis Anovulation :Aetiology and Management Premature ovarian failure Serum estradiol < 50 pg/ml and FSH > 40 IU/ml on repeated occasions 10% of secondary amenorrhea Few cases reported, where high dose estrogen or HMG therapy resulted in ovulation Sometimes immuno therapy may reverse autoimmue ovarian failure Rarely spont. ovulation (resistant ovaries) Treatment: HRT (osteoporosis, atherogenesis) Anovulation :Aetiology and Management Gonadal dysgeneis Chromosomally incompetent - Classic turner’s syndrome (45XO) - Turner variants (45XO/46XX),(46X-abnormal X) - Mixed gonadal dygenesis (45XO/46XY) Chromosomally competent - 46XX (Pure gonadal dysgeneis) - 46XY (Swyer’s syndrome) Anovulation :Aetiology and Management Gonadal dysgenesis Classic Turner’s Turner Variant True gonadal Dysgenesis Mixed Dysgenesis phenotype Female Female Female Ambiguous Gonad Streak Streak Streak - Streak - Testes Hight Short - Short - Normal Tall Short Somatic stigmata karyotype Classical XO ± Nil XX/XO or 46-XX(Pure) abnormal 46-XY X (Swyer) Anovulation :Aetiology and Management ± XO/XY Turner’s syndrome • Sexual infantilism and short stature. • Associated abnormalities, webbed neck,coarctation of the aorta,high-arched pallate, cubitus valgus, broad shield-like chest with wildely spaced nipples, low hairline on the neck, short metacarpal bones and renal anomalies. • High FSH and LH levels. • Bilateral streaked gonads. • Karyotype - 80 % 45, X0 - 20% mosaic forms (46XX/45X0) • Treatment: HRT Anovulation :Aetiology and Management Turner’s syndrome (Classic 45-XO) Mosaic (46-XX / 45-XO) Anovulation :Aetiology and Management Ovarian dysgenesis Anovulation :Aetiology and Management Androgen insensitivity Testicular feminization syndrome X-linked trait Absent cytosol receptors Normal breasts but no sexual hair Normal looking female external genitalia Absent uterus and upper vagina Karyotype 46, XY Male range testosterone level Treatment : gonadectomy after puberty + HRT Anovulation :Aetiology and Management Physiological Menarchy Peri-menopause/ menopause Pregnancy Breast feeding Anovulation :Aetiology and Management 20% of women are irregular cycles Greatest variability found in years following menarche and those preceding menopause First 5-7 years post menarche are time of increasing regularity and cycle shortening to normal reproductive pattern Most consistent cycles between the ages of 20 and 30 Highest rate of anovulation is <20 and >40 Anovulation :Aetiology and Management Hormonal Changes with Established Menopause FSH and LH levels undergo an accelerated rise in the last 2 to 3 years before menopause, with estrogen levels declining only within approximately 6 months before menopause. After menopause, when ovarian follicles are depleted, FSH and LH levels continue to rise. Eventually, there is a 20-fold increase in FSH levels and an approximately threefold increase in LH levels, both of which peak in the first 1 to 3 years after menopause In comparison, ovarian estrogen production does not continue beyond menopause, when ovarian follicles and their estrogenproducing granulosa cells are depleted Anovulation :Aetiology and Management Lactational amenorrhea Elevated prolactin levels and a reduction of gonadotropin-releasing hormone from the hypothalamus during lactation suppress ovulation This leads to a reduction in luteinizing hormone (LH) release and inhibition of follicular maturation Ovulation usually returns after 6 months despite continuous nursing Anovulation :Aetiology and Management Drugs OCP Antipsychotic Anovulation :Aetiology and Management STEROIDAL CONTRACEPTION oestrogens and progestogens based The oestrogen in most pills The 'traditional' progestogens ethinyl estradiol using the lowest possible ethynodiol, levonorgestrel and norethisterone The newer progestogens desogestrel (DSG), gestodene (GSD) and norgestimate bind more specifically to progesterone receptors Anovulation :Aetiology and Management STEROIDAL CONTRACEPTION Modes of action Inhibition of ovulation due to negative feedback on the hypothalamo-pituitaryovarian axis Induction of changes in cervical mucus, endometrium, myometrium and fallopian tubes makes them hostile to sperm and unfavourable for ovum transplant and implantation Anovulation :Aetiology and Management Psychotropic Medications Antipsychotics may block dopamine receptors in the pituitary prolactin-secreting cells and prevent dopamine-induced reduction of prolactin release Hyperprolactinemia can result in galactorrhea, amenorrhea, irregular menses, and anovulation; in men, impotence and azoospermia, with or without lactation and gynecomastia, can occur. The treatment of choice is reduction of the antipsychotic dosage or discontinuation of therapy. If adjustments to the antipsychotic dosage fail to resolve symptoms, the dopamine agonists bromocriptine and amantadine may be tried. Anovulation :Aetiology and Management INVESTIGATION Anovulation :Aetiology and Management Anovulation :Aetiology and Management Hypogonadotrophic hypogonadism A careful history surgery, radiotherapy, massive haemorrhage, lack of smell, exercise, and eating habits a body mass index measurement will reveal the cause. concentrations of luteinising hormone, follicle stimulating hormone, and estradiol will be low Anovulation :Aetiology and Management Hyperprolactinaemia A serum prolactin concentration of > 1000 IU/l is diagnostic and usually indicates a microadenoma. MRI or CT should be arranged to detect whether a macroadenoma is present. Patients with a macroadenoma must have their visual fields checked Anovulation :Aetiology and Management Hyperprolactinemia LH and FSH concentrations are usually at the lower end of the normal range with a low estradiol concentration. Test for hypothyroidism and pregnancy In hypothyroidism thyrotropin releasing hormone may stimulate prolactin secretion in addition to thyrotropin releasing hormone from the anterior pituitary Anovulation :Aetiology and Management Polycystic ovary syndrome A transvaginal ultrasound scan of the pelvis will confirm the diagnosis. In 80% of women testosterone concentration are > 2.4 nmol/l LH concentrations are raised (> 10 IU/l) in 45-70% of women with the syndrome Anovulation :Aetiology and Management Management of anovulation Treating specific causes Anovulation :Aetiology and Management Change of weight Women with polycystic ovary syndrome who are overweight (body mass index > 30) should be advised to lose weight. Exercise, weight loss- reduces insulin and free testosterone levels, resulting in improved menstrual regularity, ovulation, and pregnancy rates. Anovulation :Aetiology and Management Change of weight Women who are underweight (body mass index < 20) should be encouraged to gain weight No infertility treatment should be offered until their body mass has returned to the lower limits of normal. Anovulation :Aetiology and Management Hyperprolactinaemia Bromocriptine is safe and commonly used. starting dose of 1.25 mg (taken with food) at night for the first fortnight and then increased to 2.5 mg for another fortnight. The prolactin level should be checked, and if the level is below 1000 IU/l, the dose should be maintained. Anovulation :Aetiology and Management Side effects postural hypotension, nausea, vertigo, headache Cabergoline and quinagolide are newer long acting dopamine agonists with fewer side effects. Once prolactin < 1000 IU/l associated with ovulation in 70-80% of women Anovulation :Aetiology and Management Hypothyroidism In hypothyroidism thyrotropin releasing hormone may stimulate prolactin secretion in addition to thyrotropin releasing hormone from the anterior pituitary Correction of the hypothyroidism with thyroxine replacement allows thyroid stimulating hormone and prolactin levels to return to normal, releasing the suppression to gonadotrophin secretion and ovulation Anovulation :Aetiology and Management Antioestrogen treatment: Clomifene Clomifene acts by blocking oestrogen receptors in the pituitary leads to an increased production of follicle stimulating hormone, which then stimulates development of one or more dominant follicles Anovulation :Aetiology and Management Clomiphene Citrate - dose regimen After spontaneous menses or the induction of menses with a progestin withdrawal, clomiphene is started on cycle day 3, 4, or 5 at 50 mg daily for 5 days. Get Progesterone checked on D21 Not ovulating Maximum recommended no of ovulatory cycles to 100mg-150mg per day -6 Anovulation :Aetiology and Management Clomiphene Citrate Ultrasound monitoring, because risk of ovarian hyperstimulation syndrome 70% of women with PCO will ovulate conception rate of 40-60% at six months. The incidence of twins is around 10%, and triplets 1%. Anovulation :Aetiology and Management Downsides to Clomiphene Unpleasant side effects irritability, hotflashes, abdominal discomfort, visual disturbances Multiple pregnancies Endometrial hypotrophy esp. when used for > 6 months Hostile sperm cervical mucous interactions Anovulation :Aetiology and Management Anovulation :Aetiology and Management Tamoxifen and Oligo-ovulation Dose of 20-40mg twice daily from day 2-5 Similar side effects SERM with some estrogenic effects on the endometrium May improve sperm/mucus interactions Similar rates of ovulation and pregnancy OHSS rare and usually resolves on its own Incidence of twins slighty increased Boostanfar et al 2001 Anovulation :Aetiology and Management Aromatase Inhibitors • • Letrozole: an oral, reversible, steroidal aromatase inhibitor. no- Dose: 2.5 mg/d from day 3-7 Results in ovulation in 9/12 in Clomiphene resistant PCO Addition of letrozole may reduce dose and increase response to FSH Anovulation :Aetiology and Management Letrozole Mechanism of action: 1. Release of the estrogen negative feedback, increase GnTR, stimulate ovarian follicle development 2. Increase sensitivity of follicles to FSH. Advantages of letrozole over CC: Because of the short half life (45h) & absence of ER depletion No effect on the endometrial thickness or cervical mucous Letrozole is effective for increasing follicle recruitment in UI (Mitwally & Casper,2000) Letrozole can replace CC in patients with UI undergoing ovulation induction & IUI (Sammour,2001) . Anovulation :Aetiology and Management Metformin doses of 1500 mg a day similar effect to weight loss) NB increase dose slowly Lowers insulin Lowers testosterone Increases SHBG Improves HDL:LDL ratio Anovulation :Aetiology and Management Metformin Systematic review of metformin for PCO: 12 RCT’s, 2 cohort studies and 16 case series Metformin alone improves menstrual cyclicity Metformin plus CC improves pregnancy rates Costello, Eden 2003 Anovulation :Aetiology and Management Surgical induction Laparoscopic ovarian diathermy or "drilling" has replaced wedge resection of the ovaries in women with polycystic ovary syndrome. At laparoscopy, five to six diathermy or laser punctures are made in the ovary. If too much ovarian tissue is destroyed there is a potential risk of premature ovarian failure in the future, although this risk is still being evaluated. Anovulation :Aetiology and Management Ovarian Cautery for PCO 8 trials comparing ovarian drilling to other interventions ( CC, FSH, GnRHa/FSH) Similar miscarriage rate, 22% Multiple pregnancy rates post cautery FSH seems reduced 0% vs 10% Anovulation :Aetiology and Management Human Gonadotropins – Endocrinology Overview Link between hypothalamic-pituitary axis and the ovary Required at threshold levels for follicular development Anovulation :Aetiology and Management Human Gonadotropins Control of gonadotropin release occurs through pulsatile hypothalamic production of gonadotropin releasing hormone (GnRH) Pulses vary over the course of the menstrual cycle. The timing and amplitude of pulses determine gonadotropin release from the pituitary. Anovulation :Aetiology and Management Types of Gonadotropins In females, the reproductive axis is responsive to two main gonadotropin types: Follicle Stimulating Hormone (FSH) Luteinizing Hormone (LH) Anovulation :Aetiology and Management Pulsatile gonadotrophin releasing hormone May be suitable in hypothalamic cause of amenorrhoea Mechinical device delivers a pulse of gonadotrophin releasing hormone subcutaneously every 90 minutes, and this usually leads to unifollicular ovulation. Local reactions may occur at the injection site. Conception rates are similar to those in the normal population at around 20-30% per cycle and 8090% after 12 months' use Anovulation :Aetiology and Management Exogenous Gonadotropin Therapy Exogenous Gonadotropin Therapy Patient Types Substitution - hypogonadal women Stimulation – women with hypothalamic dysfunction Regulation - oligo-anovulatory women Hyperstimulation therapy – women undergoing Assisted Reproductive Technology procedures Anovulation :Aetiology and Management Exogenous Gonadotropin Therapy • • Objective: simulate a normal menstrual cycle Action: override the hypothalamicpituitary axis and direct: the onset and duration of follicular development the timing and number of follicles that reach maturity the production of gonadal steroids Anovulation :Aetiology and Management Follicle stimulating hormone injections used in women with hypothalamic-pituitary causes of anovulation, and for women with polycystic ovary syndrome who have failed to respond to or conceive using clomifene. monitored by reproductive specialists with access to ultrasonography and tertiary care facilities complicated by ovarian hyperstimulation syndrome and high order multiple pregnancy Anovulation :Aetiology and Management Approved urinary derived gonadotropins and recombinant gonadotropins Trade Name Established Name Pergonal Menotropins (LH, FSH) Menotropins (LH, FSH) Menotropins (LH, FSH) Urofollitropin (FSH) Humegon® Repronex Metrodin HP (Fertinex) Bravelle Gonal-F Follistim Urofollitropin (FSH) Follitropin alpha (FSH) Follitropin beta (FSH) Anovulation :Aetiology and Management Types of Gonadotropin Therapy Marketed Recombinant human gonadotropins follitropin alfa (Gonal-f®) follitropin beta, (Follistim®) chorionic gonadotropin alfa (Ovidrel®). Anovulation :Aetiology and Management A Typical U.S. Gonadotropin Treatment Protocol Baseline serum estradiol (E2) level Baseline ultrasound scan Administer daily for 7 - 10 days Repeat E2 level and ultrasound approximately every 2 to 3 days until follicular maturity is achieved Administer human chorionic gonadotropin (hCG) to induce ovulation Anovulation :Aetiology and Management FSH administration regimens Chronic Low Dose (CLD): S. Franks et al. 75 IU Days 7 14 hCG 150 IU 112.5 IU 75 IU 21 28 Step Down (SD): B. Fauser et al. 150 IU 112.5 IU 75 IU hCG Foll. ³ 10 mm Sequential (SE): J.N. Hugues et al. 150 IU 112.5 IU 75 IU 6 ½ 75 IU 12 Foll. ³ 14 mm hCG Anovulation :Aetiology and Management Cumulative pregnancy rates for hypogonadotropic anovulatory women treated with gonadotropins. (From Lunenfeld B, Insler V. Human gonadotropins. In: Wallach EE, Zacur HA, eds. Reproductive medicine and surgery. St. Louis: Mosby-Year Book, 1995:617) Pregnancy rate Study Fleming 1988 Homburg 1990 Hompes 1986 Total GnRH-a + Gonadotropin 14/40 Gonadotropin 5/38 5/57 6/65 0/5 4/6 19/102 12/106 Nugent et al Cochrane 2000 OHSS rate Study Bachus 1990 Homburg 1990 Hompes 1986 Total GnRH-a + Gonadotropin 1/33 Gonadotropin 2/26 8/57 5/65 0/3 0/3 9/93 7/94 Nugent et al Cochrane 2000 Ovarian hyperstimulation syndrome (OHSS) The ovarian hyperstimulation syndrome is an iatrogenic complication of ovulationinduction therapy incidence of 0.5 to 5 percent among patients undergoing ovulation-induction therapy. Anovulation :Aetiology and Management Ovarian hyperstimulation syndrome (OHSS) Causes: 1. increasing stimulated follicles and retrieved oocytes; 2. presence of PCOS; 3. high estrogen level; 4. HCG injection; Pathophysiology: 1. local and systemic increase in capillary permeability; 2. Inflammatory responses; Anovulation :Aetiology and Management Clinical finding: OHSS (1) Mild OHSS (a) Grade 1, abdominal distention and discomfort (b) Grade 2, plus nausea, vomiting, and/or diarrhea associated with ovarian enlargement of 5-12 cm (2) Moderate OHSS (a) Grade 3, manifestations of the mild form plus US evidence of ascites (3) Severe OHSS (a) Grade 4, features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax or breathing difficulties (b) Grade 5, changes in blood volume, increased blood viscosity due to hemoconcentration, coagulation abnormalities and impaired renal function with oliguria Golan et al., Obstet Gynecol Surv 1989; 44:430-40 Anovulation :Aetiology and Management Ovarian hyperstimulation syndrome (OHSS) Examinations: 1. Complete blood account, renal and liver function; 2. Prothrombin time, partial thromboplastin time; 3. Chest X-ray; 4. Trans-vaginal ultrasound; 5. Oxygen saturation; 6. Fluid balance; 7. Serum HCG measurement; 8. Pelvic exam is contraindicated; Treatment: 1. Prevention of OHSS; 2. Follow-up: Vital signs, fluid intake and output measurement; 3. Admission to hospital; Anovulation :Aetiology and Management Management of OHSS Mild Moderate No need to admit Increase oral fluid intake Follow up at regular intervals and report if symptoms worsen Admit to hospital and assess daily Start thromboprophylaxis and maintain until patient is discharged Monitor liver function, urea and electrolytes, full blood count, and clotting Severe Strict fluid balance with input of 3 L or more May need intravenous albumin Drain ascites or pleural effusion if symptomatic Anovulation :Aetiology and Management Anovulation :Aetiology and Management References Peter Braude Paula Rowell, Assisted conception. III—Problems with assisted conception BMJ 2003;327:920-923 (18 October), doi:10.1136/bmj.327.7420.920 Anovulation Diana Hamilton-Fairley, Alison Taylor BMJ 2003;327:546-549 (6 September), doi:10.1136/bmj.327.7414.546 Marken PA, Haykal RF, Fisher JN. Management of psychotropic-induced hyperprolactinemia.Clin Pharm. 1992 Oct;11(10):851-6 ACOG Practice Bulletin; Management of Infertility Caused by Ovulatory Dysfunction; ACOG NUMBER 34, FEBRUARY 2002 Anovulation :Aetiology and Management