Nonclassic CAH Nonclassic CAH is due to partial de \201 ciency of 21A-hydroxylase. Glucoco rticoid and aldosterone production are normal, but there is over- production of 17OHP and, thus, androgens. Patients present with hirsutism (60%), acne (33%), and oligomenorrhea (54%), often around t he onset of puberty. Only 13% of women present with subfertility. One-third of women have polycystic ovaries on US, and adrenal inci- dentalomas or hyperplasia is seen in 40%. The nonclassic form is asymptomatic in men. The effect of nonclassic CAH on men fertility is unknown. 47-Draznin-Chap47.indd 241 4/1/2011 5:34:03 PM CHAPTER 47 Congenital adrenal hyperplasia 242 Laboratory evaluation Because of the diurnal variation in adrenal hormonal secretion, all i nvesti- gations should be performed in the morning. Diagnosis of non-classic CAH \200\22417OHP measurement Timing of measurement \200 Screen in the follicular phase of the menstrual cycle. 17OHP is produced by the corpus luteum, so false-positive results may occur if measured in the lutea l phase of the cycle. Must be measured A.M. to avoid false-negative results, as 17OHP has a diurnal variation similar to that of ACTH ACTH stimulation test \200 Measure 17OHP 30 minutes after ACTH administration. \200 An exaggerated rise in 17OHP is seen in nonclassic CAH. \200 17OHP level <1000 ng/dL post-AC TH excludes the diagnosis. \200 Most patients have levels >1500 ng/dL. \200 Levels of 1 000 \200\2231500 ng/dL suggest heterozygosity or nonclassic CAH. \200 Cortisol response t o ACTH stimulation is usually low to normal. Other investigations Androgens In poorly controlled classic CAH in women, testosterone and androstene- dione levels may be in the adult male range. Dehydroepiandrosterone sul- fate l evels are usually only mildly, and not consistently, elevated in CAH. Circulating testoster one and, particularly androstenedione, are elevated in nonclassic CAH, but there is a large overlap with levels seen in PCOS so serum androgen concentrations cannot be used to distin guish between the disorders. Renin Plasma renin levels are markedly elevated in 75% of patients with inad- equately trea ted classic CAH, re \202 ecting de \201 cient aldosterone production. A proportion of wom en with nonclassic CAH may also have mildly elevated renin concentrations. ACTH \200 Greatly elevated in poorly controlled classic CAH \200 Usually normal levels in nonclassic CAH b See Table 47.1 for a list of enzyme de \201 ciencies in CAH. 47-Draznin-Chap47.indd 242 4/1/2011 5:34:03 PM LABORATORY EVALUATION 243 Table 47.1 Enzyme de \201 ciencies in CAH Enzyme de \201 ciency Classic 21A- hydroxylase Incidence (per births) Clinical features 1:10 000 \200\2231:15 000 Salt wasting, ambiguous genitalia in females, precocious pubarche in males Nonclassic 21A-hydroxylase (partial de \201 ciency) 11B-hydroxylase 1:27 \200\2231:1000 Hirsutism, oligomenorrhea in pubertal girls, asymptomatic in boys 1:100 000 Ambiguous genitalia, virilization, hypertension 3B-hydroxylase Rare Mild virilization, salt wasting in severe cases 17A-hydroxylase Rare Delayed puberty in females, pseudohermaphroditism in males, hypertension, hypokalemia 47-Draznin-Chap47.indd 243 4/1/2011 5:34:04 PM CHAPTER 47 Congenital adrenal hyperplasia 244 Management The aims of treatment of CAH in adulthood are as follows: \200 To maintain nor mal energy levels and weight and avoid adrenal crises in all patients To minimize hyperandrogenism and to restore regular menses and fertility in women To avoid glucocorticoid over-replacement \200 To treat stress with adequate extra glucoco rticoid Classic CAH Prednisone A total dose is 5 \200\2237.5 mg/day. This is given in one dose, eit her in the morn- ing or at bedtime depending on the authority. There are no controlled stud ies comparing the two regimens. The evening dosing is to suppress the early-morning peak of ACTH and thus androgen secretion. The opti- mum dose is the minimum dose required to norma lize serum androgens. Occasional patients who are not controlled on prednisone may be treated with nocturnal dexamethasone instead (0.25 \200\2230.5 mg). Other therapies As with other forms of adrenal insuf \201 ciency, glucocorticoid doses sho uld be doubled during illness, as discussed in detail elsewhere ( b p. 337, 363). Three-quarters of patients are salt wasters and thus require mineralo- corticoid replacemen t therapy. Fludrocortisone in a dose of 50 \200\223200 mcg/ day is given as a single daily dose. The aim is to keep plasma renin levels in the mid-normal range. Bilateral adrenalectomy may very occasionally be considered in patients with severe virilization resistant to conventional therapy. Experimental therapies Trials have been performed using a combination of low-dose hydrocor- tisone, \202 udrocortisone, testolactone (an aromatase inhibitor), and \202 uta- mide (antiandrogen) in children. This 4-drug regimen appears to improve \201 nal height and mi nimize glucocorticoid side effects with no signi \201 cant adverse effects. However, long- term effects are currently unknown. Pregnancy Screen the patient and her partner prior to pregnancy and give genetic advice. If the partner is a carrier, there is a 50% risk of having an affected child (1 in 63 is a ca rrier of the 21OH gene). Nonclassic CAH Oligo- and amenorrhea are treated with glucocorticoid therapy \200\224e.g., noctural dexamethasone 0.25 \200\2230.5 mg or prednisone 2.5 \200\2235 mg/day, may be used. Slightly higher doses may be required to normalize ovulatory function. If fertility is not desired, symptoms may be treated with OCPs and antiandrogen. 47-Draznin-Chap47.indd 244 4/1/2011 5:34:04 PM MANAGEMENT 245 Hirsutism and acne may be treated using OCPs ( b see Management, p. 237). Spironolactone sh ould be avoided because of the potential risk of salt wasting and thus hyperreninemia. If the plasma renin level is elevated, then \202 udrocortisone given in a dose suf \201 cient to normalize renin concentrations may improve adrenal hyperandrogenism. Men do not usually require treatment. The occasional man may need glucocorticoids to treat subfertility. Management of pregnancy in CAH Indications for prenatal treatment \200 Maternal classic C AH: Screen patient and partner using basal ACTH- stimulated 17OHP levels ( b see Investigations, p. 242). If levels are elevated, proceed to genotyping. If heterozygote, then prenatal treatment of the fetus is recommended. \200 P revious child from same partner with CAH Aims of prenatal treatment ( b see Fig. 47.2 ) The aim is to prevent virilization of an aff ected female fetus. Treatment (commenced before 10 weeks gestation) Dexamethasone (20 mcg/kg maternal body weig ht) in 3 divided doses a day crosses the placenta and reduces fetal adrenal hyperandrogenis m. Discontinue treatment if the fetus is male. Outcome From 50 to 75% of affected women do not require reconstructive surgery. Start dexamethasone 20 mcg/kg per day (prepregnancy weight) Best results if started at 4 \200\2236 weeks, certainly before week 9 of gestation Chorinic villus sampling at 10 \200\22312 weeks for fetal karyotype DNA analysis 46XY 46XX, affected (1 in 8) 46XX, unaffected Discontinue treatment Continue treatment to term Monitor maternal BP, weight, glycosuria, HbA, c plasma cortisol, DHEAS, \224 androstenedio ne every 2 months Fig. 47.2 Prenatal treatment protocol. 47-Draznin-Chap47.indd 245 4/1/2011 5:34:04 PM CHAPTER 47 Congenital adrenal hyperplasia 246 Complications There are no known fetal congenital malformations or neonanatal compli- catio ns from dexamethasone treatment. Subtle effects of glucocorticoids on neuropsychological function are unknown. No signi \201 cant long-term follow-up studies on treated children have been published to date. Maternal complications of glucocorticoid excess include mood swings, weight gain, gestation al diabetes, and hypertension. Monitor maternal weight, blood pressure, fasting plasma gluc ose, and urinary glucose. There is debate about whether women with nonclassic CAH should be offered prenatal treatmen t with dexamethasone. There have been no cases of women with nonclassic CAH giving birth to a virilized female. Additionally, the estimated risk of conceiving an infant with classic CAH is 1:1000. As the risk of fetal virilization is therefore low, dexamethasone treatment of this group of wome n seems unwarranted. However, these infants should be screened in the neonatal period by me asuring 17OHP levels. Monitoring of treatment Annual follow-up is usually adequate in adults. \200 Clinical ass essment: Look for evidence of hyperandrogenism and glucocorticoid excess. Amenorrhea in wom en usually suggests inadequate therapy. Measure BP. 17OHP: Aim for a mildly elevated level (about 2 \200\2234 x normal). Normalizing 17OHP will result in complications from supraphysiological doses of glucocortic oids. Plasma rennin: Aim for renin in mid-normal range. Hyperandrogenism will be dif \201 cult t o control if the patient is mildly salt depleted (ACTH production stimulated by hypovolemia ). Androgens: Aim to normalize serum testosterone/androstenedione taken before A.M. steroids. Consider bone density, which may be reduced by supraphysiological steroid doses. In females: \200 Good control ensures fertility. \200 Testes should be intermittently c hecked for masses \200\224adrenal cell rests. 47-Draznin-Chap47.indd 246 4/1/2011 5:34:04 PM PROGNOSIS 247 Prognosis Adults with treated CAH have a normal life expectancy. Improvement in medical and surgical care has also improved quality of life (QoL) for most sufferers. However, there a re a few unresolved issues. Height Despite optimal treatment in childhood, patients with CAH are, on aver- age, signi \201 cantly shorter than their predicted genetic height. Studies sug- gest that this may be due to overtreatment with glucocorticoids during infancy. Fertility Fertility remains reduced in women with CAH, particularly in salt wasters, from f actors including inadequate vaginal introitus and anovulation sec- ondary to both hyperandr ogenism and high 17OHP levels. Fertility may also be affected in men with poorly controlled classic CAH. Adrenal incidentalomas and testicular adrenal rest tumors Benign adrenal adenomas have been reported in up to 50% of patients with classic CAH. Men with CAH may develop adrenal rests . These are ACTH-responsive and should be treated by optimizing glucocorticoid therapy. Occasionally, adults with nonclassic CAH develop adrenal adenomas or testicular rests and should then be started on steroids. Further reading Cabrera MS, Vogiatzi MG, New MI (2001). Long-term outcome in adult males wi th classic congeni- tal adrenal hyperplasia. J Clin Endocrinol Metab 86(7):3070 \200\223307 8. Joint LWPES/ESPE CAH Working Group (2002). Consensus statement on 21-hydroxylase de \201 c ice- ncy from the Lawson Wilkins Pediatric Endocrine Society and the European Society for P ediatric Endocrinology. J Clin Endocrinol Metab 87(9):4048 \200\2234053. Merke DP (2008). Approach to the adult with congenital adrenal hyperplasia due to 21-hydrox ylase de \201 ciency. J Clin Endocrinol Metab 93:653 \200\223660. New MI (2006). Extensive clinical experience: nonclassical 21-hydroxylase de \201 ciency. J Clin Endocrinol Metab . 91(11):205 \200\223214. New MI, Carlson A, Obeid J, et al. (2001). Prenatal diagnosis for congenital adrenal hyperp lasia in 532 pregnancies. J Clin Endocrinol Metab 86(12):5651 \200\2235757. Ogilvie CM, Crouch NS, Rumsby G, et al. (2006). Congenital adrenal hyperplasia in adults: a review of medical, surgical and psychological issues. Clin Endocrinol 64:2 \200\22311. Premawaradhana LDKE, Hughes IA, Read GF, et al. (1997). Longer term outcome in females with congenital adrenal hyperplasia: the Cardiff experience. Clin Endocrinol 46:327 \200\223332 . Speiser PW, White PC (2003). Congenital adrenal hyperplasia. N Engl J Med 349(8):776 \200 \223788. Ehrmann DA, Rychlik D (2003). Pharmacological treatment of polycystic ovary syndrome. Semin Reprod Med 21(3):277 \200\223283. Ledger WL, Clark T (2003). Long-term consequences of polycystic ovary syndrome. Royal Colle ge of Obsterics and Gynecology Guideline number 33. 47-Draznin-Chap47.indd 247 4/1/2011 5:34:04 PM CHAPTER 47 Congenital adrenal hyperplasia 248 Lord JM, Flight IHK, Norman RJ (2003). Insulin-sensitizing drugs for polycystic ovary syndr ome. Cochrane Database Syst Rev 2003(3):CD003053. Neithardt AB, Barnes RB (2003). The diagnosis and management of hirsutism. Semin Reprod Med 21(3):285 \200\223293. Nestler JE (2008) Metformin for the treatment of the polycystic ovary syndrome. N Engl J Me d 358(1):47 \200\22354. Pierpoint T, McKeigue PM, Isaacs AJ, et al. (1998). Mortality of women with polycystic ovar y syn- drome at long-term follow-up. J Clin Epidemiol 51(7):581 \200\223586. Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group (2004). Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Hu m Reprod 19:41 \200\22347. Tsilchorozidou T, Overton C, Conway GS (2004). The pathophysiology of polycystic ovary syn- drome. Clin Endocrinol 60(1):1 \200\22317. 47-Draznin-Chap47.indd 248 4/1/2011 5:34:04 PM EPIDEMIOLOGY AND PATHOLOGY 249 Androgen-secreting tumors De \201 nition These rare tumors of the ovary or adrenal gland may be benign or malig- nan t and cause virilization in women through androgen production. Epidemiology and pathology Androgen-secreting ovarian tumors Three-quarters develop before the age of 40 years. They account for 0.4% of all ovarian tumors. 20% are malignant. Tumors are variable in size. The larger they are, the more likely they are to be malignant. They are rarely bilateral. There are two major types: \200 Sex cord stro mal cell tumors often contain testicular cell types. \200 Adrenal-like tumors often conta in adrenocortical or Leydig cells. Other tumors, e.g., gonadoblastomas and teratomas, may a lso on occasion present with virilization. Androgen-secreting adrenal tumors Half of these tumors develop before the age of 50 years. Larger tumors, particularly >6 cm, are more likely to be malignant. 48-Draznin-Chap48.indd 249 3/31/2011 2:53:32 PM CHAPTER 48 Androgen-secreting tumors 250 Clinical features Onset of symptoms \200 Usually recent onset of rapidly progressive symptoms Hyperandrogen ism \200 Hirsutism of varying degree, often severe (Ferriman \200\223Gallwey score) ( b s ee Table 45.2, p. 225). Male-pattern balding and acne are also common. Usually oligo- or amenorrhea \200 Infertility may be a presenting feature. Virilization ( b Box 45.1, p. 224) \200 Indicates severe hyperandrogenism is associated w ith clitoromegaly and is present in 98% of women with androgen-producing tumors. Not usually a feature of PCO S Other \200 Abdominal pain \200 Palpable abdominal mass \200 Ascites \200 Symptoms a nd signs of Cushing \200\231s syndrome are present in 50% of females with adrenal tumors. Laboratory evaluation b See Fig. 48.1. Short history of hirsutism and virilization (weeks/months) Serum testosterone >5 \206\221 nmol/L DHEAS \206\221 in adrenal tumors Androstenedione \206\221 in ovarian tumors 17 OHP may \206\221 be in both. Exclude CAH UFC \206\221 in adrenal tumors Ovarian US MRI adrenal glands and ovaries only if \210\222ve imaging Selective venous sampling Fig. 48.1 Investigation of androgen-secreting tumors. 48-Draznin-Chap48.indd 250 3/31/2011 2:53:32 PM PROGNOSIS 251 Management Surgery \200 Adrenalectomy or ovarian cystectomy/oophorectomy \200 Curative in benign l esions Adjunctive therapy Malignant ovarian and adrenal androgen-secreting tumors are often resist - ant to chemotherapy and radiotherapy. Prognosis Benign tumors Prognosis is excellent. Hirsutism improves postoperatively, but cli torome- galy, male-pattern balding, and deep voice may persist. Malignant tumors \200 Adrenal tumors: 20% 5-year survival. Most patients have metastatic disease at the time of surgery Ovarian tumors: 30% disease-free survival; 40% overall 5-year survival Further reading Hamilton-Fairley D, Franks S (1997). Androgen-secreting tumors. In Sheaves R, Jenkins PJ, Wass JAH (Eds.), Clinical Endocrine Oncology . Oxford: Blackwell Science, pp . 323 \200\223329. 48-Draznin-Chap48.indd 251 3/31/2011 2:53:32 PM CHAPTER 49 Menstrual function disorders 252 Menstrual function disorders De \201 nitions Oligomenorrhea is de \201 ned as the reduction in the frequency of menses to <9 periods a year. Primary amenorrhea is the failure of menarche by the age of 16 years. Prevalence is 70.3% Secondary amenorrhea refers to the cessation of menses for >6 months in women who had previously menstruated. Prevalence is 73 \200\2236%. Many disorders may present with either primary or secondary amenorrhea. The normal menstrual cycle is presented in Fig. 48.1. Pituitary cycle LH FSH Ovarian cycle Maturation of follicle Corpus luteum Ovulation E2 P Endometrial cycle M \210\22212 \210\2228 \210\2224 +4 +8 +12 0 Follicular phase Luteal phase Ovulatory phase Fig. 49.1 The normal menstrual cycle. 49-Draznin-Chap49.indd 252 3/31/2011 2:54:24 PM CLINICAL EVALUATION 253 Clinical evaluation History \200 Estrogen de \201 ciency, e.g., hot \202 ushes, reduced libido, and dyspar eunia. \200 Hypothalamic dysregulation, e.g., exercise and nutritional history, body weig ht changes, emotional stress, recent or chronic physical illness \200 In primary amenorrh ea \200\224history of breast development, history of cyclical pain, age of menarche of mother and sisters In secondary amenorrhea \200\224duration and regularity of previous menses, family history of early menopause, or familial autoimmune disorders, or galactosemia Anosmia may indicate Kallmann syndrome from GnRH de \201 ciency. \200 Hirsutism or acne \200 Galactorrhea \200 History suggestive of pituitary, thyroid, or adrenal dysfunction \200 Drug history \200\224e.g., causes of hyperprolactinemia, chemotherapy, hormonal contraception, recreational drug use Obstetric and surgical history Physical examination \200 Height, weight, body mass index (BMI) \200 Features of Turner \200\231s syndrome or other dysmorphic features \200 Secondary sex characteristics \200 Galactorrhea \200 Evidence of hyperandrogenism or virilization \200 Evidence of thyro id dysfunction \200 Anosmia, visual \201 eld defects For causes, b see Box 49.1. 49-Draznin-Chap49.indd 253 3/31/2011 2:54:24 PM CHAPTER 49 Menstrual function disorders 254 Box 49.1 Causes of amenorrhea Physiological \200 Pregnancy and lactation \200 Postmenopause Iatrogenic \200 Depomed roxyprogesterone acetate \200 Levonorgestrel-releasing intrauterine device \200 Progest erone-only pill \200 Pathological \200\224primary \200 Chromosomal abnormalities \200 \22450% Turner \200\231s syndrome \200 Other X chromosomal disorders Secondary hypogonadism \200\22425% Kallmann \200\231s syndrome \200 Pituitary disease \200 Hypothalamic amenorrhea Genitourinary malformations \200\22415% Imperforate hymen \200 Congenital absence of uterus, cervix, or vagina Other \200\22410% Androgen insensitivity syndrome \200 CAH \200 PCOS \200 Galactosemia Most causes of secondary amenorrhea can cause primary amenorrhea. \200 Pathological \200 \224secondary \200 Ovarian \200\22470% PCOS \200 Premature ovarian failure Hypothalamic \200\22415% Weight loss \200 Excessive exercise \200 Physical or psychological stress \200 Cranio pharyngioma \200 In \201 ltrative lesions of the hypothalamus \200 Drugs e.g., opiates Pituitary \200\2245% Hyperprolactinemia \200 Hypopituitarism \200 Isolated gonadotropin de \201 ciency Uterine \200\2245% Intrauterine adhesions Other endocrine disorders \200\2245% Thyroid dysfunction \200 Cushing \200\231s syndrome \200\223 Other causes of hyperandrogenism 49-Draznin-Chap49.indd 254 3/31/2011 2:54:24 PM LABORATORY EVALUATION 255 Laboratory evaluation b See Fig. 49.2. Is it primary or secondary ovarian dysfunction? FSH, LH, estradiol, prolactin Transvaginal US: \200 Ovarian and uterine morphology \200 \224exclude anatomical abnormalities, PCOS, and Turner \200\231s syndrome Endometrial thickness to assess estrogen status Other tests, depending on clinical suspicio n, are as follows: \200 Induce withdrawal bleed with progesterone (e.g., 5 \200\22310 mg medroxyprogesterone acetate daily for 7 days). If a bleed occurs, there is adequate estroge n priming and endometrial development. Serum testosterone in the presence of hyperandrogenism \200 Thyroid function tests if any evidence of hyper- or hypothyroidism \200 Karyotype in ovarian failure or if Turner \200 \231s syndrome or androgen insensitivity syndrome suspected. MRI of the pituitary if LH, FSH low or in the presence of hyperprolactinemia. Exclude structural abnormality History/ physical exam Exclude preg nancy FSH, LH, prolactin FSH, LH \206\223 Prolactin \206\221 FSH >30 IU/L FSH normal Hyperprolactinemia: rule out hypothyroidism and pituitary adenoma Primary ovarian failure: Hypog onadotrophic hypog onadism: rule out pituitary adenoma PCOS check karyotype Fig. 49.2 Investigation of amenorrhea. 49-Draznin-Chap49.indd 255 3/31/2011 2:54:24 PM CHAPTER 49 Menstrual function disorders 256 Management Treat underlying disorder, e.g.: \200 Dopamine agonists for prolactinomas \200 Pituitary surgery for pituitary tumors \200 Weight gain in anorexia nervosa Treat e strogen de \201 ciency with low-dose estrogen/progestogen prepara- tions or OCPs. Treat infertility \200\224 b see p. 236 Further reading Baird DT (1997). Amenorrhoea. Lancet 350:275 \200\223279. Beswick SJ, Lewis HM, Stewart PM (2002). A recurrent rash treated by oophrectomy. QJM 95(9) ,:636 \200\223637. Hickey M, Balen A (2003). Menstrual disorders in adolescence: investigation and management. Hum Reprod Update 9(5):493 \200\223504. 49-Draznin-Chap49.indd 256 3/31/2011 2:54:25 PM EPIDEMIOLOGY 257 Premature ovarian insuf \201 ciency (POI) De \201 nition POI is a disorder characterized by amenorrhea, estrogen de \201 ciency, an d elevated gonadotropins developing in women <40 years as a result of loss of ovarian folli cular function. Epidemiology Incidence is 0.1% of women <30 years and 1% of those <40 years. POI accounts f or 10% of all cases of secondary amenorrhea. Causes of POI \200 Chromosomal abnormalities (60%) (see Table 50.1) Turner \200\231s syndrome (see Box 50.1 ) \200 Fragile x syndrome \200 Other x chromoso mal abnormalities Gene mutations B subunit of FSH \200 FSH receptor \200 LH receptor Autoimmune disease (20%) \200 Iatrogenic Chemotherapy \200 Radiotherapy \200 Hysterectomy Other Familial ovarian failure \200 Galactosemia \200 Enzyme de \201 ciencies, e.g., 17-hydr oxylase de \201 ciency. \200 Infections, e.g., mumps, CMV, HIV, Shigella Idiopathic ?Environmental toxin 50-Draznin-Chap50.indd 257 3/31/2011 2:58:33 PM CHAPTER 50 Premature ovarian insuf \201 ciency (POI) 258 Table 50.1 Correlation of karyotype with phenotype Karyotype Phenotype 45,X (50%) Most severe phenotype High incidence of cardiac and renal abnormalities i Prevalence of thy roiditis, in \202 ammatory bowel disease, and deafness 46,Xi(Xq) (20%) 45,X/46,XX (10%) Least severe phenotype i Mean height Spontaneous puberty and menses in up to 40% 46,Xr(X) (10%) Spontaneous menses in 33% Congenital abnormalities uncommon Cognitive dysfunction in those with a small ring chromosome i Risk of gonadoblastoma 45,X/46,XY (6%) Other (4%) Box 50.1 Turner \200\231s syndrome b Also see Turner \200\231s syndrome (p. 442). \200 Mo st common X-chromosome abnormality in females, affecting 1:2500 live female births. Result of complete or partial absence of one X chromosome. \200 Clinical features: short stature and gonadal dysgenesis. 90% of affected women have POI. Characteristic phenotype: webbed neck, micrognathia, low-set ears, high arched palate, widely spaced nipples, and cubitus valgus \200 Other associated abnor malities: aortic coarctation and other left- sided congenital heart defects, hypothyroidism , osteoporosis, skeletal abnormalities, lymphedema, celiac disease, congenital renal abnorm alities, and ear, nose, throat (ENT) abnormalities Diagnosis: lymphocyte karyotype Management in adults \200 Sex hormone replacement therapy \200 Treat complications Follow-up \200 Baseline renal US, thyroid autoantibodies \200 Annual BMI, BP, TFT, lipids, fasting blood glucose liver function \200 3- to 5-year ly echocardiogram and bone densitometry \200 Hearing loss every 5 years 50-Draznin-Chap50.indd 258 3/31/2011 2:58:34 PM PATHOGENESIS 259 Pathogenesis Failure of normal ovarian follicular response to gonadotropins leads to conseq uent failure of ovarian steroidogenesis. POI is the result of either ovarian follicle deple tion or failure of the follicles to function (resistant ovary syndrome). It may be distingu ished by ovarian US or histologically by ovarian biopsy. Treatment options are the same, so invasive techniques looking for the presence of follicles are not indicated. POI is usually permanent; however, more data show a variable intermit- tent pattern of horm one production. Additionally, <50% of karyotypically normal women with established disease produce estrogen intermittently and up to a 1/5 of women may ovulate despite high gonadotro pin levels. Spontaneous pregnancy has been reported in 5%. 50-Draznin-Chap50.indd 259 3/31/2011 2:58:34 PM CHAPTER 50 Premature ovarian insuf \201 ciency (POI) 260 Clinical presentation Amenorrhea \200 May be primary, particularly in those with chromosomal abnormalities Symp toms of estrogen de \201 ciency \200 Not present in those with primary amenorrhea \200 75% of women who develop secondary amenorrhea report hot \202 ushes, night sweats, mood changes, fatigue, or dyspareunia; symptoms may precede the onset of menstrual disturbances. Autoimmune disease \200 Screen for symptoms and signs of associated autoimmune disorders. Other \200 Past history of radiotherapy, chemotherapy, or pelvic surgery \200 Positive family history in 10% of patients Box 50.2 Autoimmune diseases and POI Autoimmune disease is responsible for 20% of all cases of POI. A second autoimmune disorder is present in 10 \200\22340% of women with autoimmune POI: \200 Addison \200\231s diseas e (10%) \200 Autoimmune thyroid disease (25%) \200 Type 1 diabetes mellitus (2%) \200 Myaesthenia gravis (2%) \200 B 12 de \201 ciency \200 Systemic lupus erythematosus (S LE) is also more common POI is present in the following: \200 60% of 5 with autoimmune po lyglandular syndrome type 1 ( b p. 198) 25% of 5 with autoimmune polyglandular syndrome type 2 ( b p. 199) Steroid cell antibodies are positive in 60 \200\223100% of patients with Addison \200\231s disease in combination with POI. Presence of positive steroid cell antibod- ies in women wi th Addison \200\231s disease confers a 40% risk of ultimately devel- oping POI. Other ovari an antibodies have no predictive value. 50-Draznin-Chap50.indd 260 3/31/2011 2:58:34 PM LABORATORY EVALUATION 261 Laboratory evaluation Serum gonadotropins \200 Diagnosis is con \201 rmed by serum FSH > 40 mIU/L (actual level depends on the assay) on at least two occasions at least 1 month apart associated with a low estrad iol. Disease may have a \202 uctuating course with high FSH levels returning to normal and later regaining of ovulatory function. LH is also elevated; FSH is usually disproportionately higher than LH. Serum estradiol leve ls \200 Usually low Karyotype \200 All women below age 40 presenting with hypergonadotr opic amenorrhea should have karyotyping performed. Women with Y-chromosomal material should be referred for bilateral gonadectomy to prevent the development of gonadoblastoma. Pelvic US \200 To identify normal ovarian and uterine morphology Transvaginal US \200 O varian volume and blood \202 ow \200 Uterine size and anatomy Bone mineral density \200 Risk of osteoporosis Screen for autoimmune disease \200 Thyroid and adrenal cortex autoantibodies. If positive, this increases the risk of progression to overt adrenal or thy roid insuf \201 ciency. Ovarian antibodies are of no proven clinical value. \200 TSH and fasting blood glucose, F BC \200 Cosyntropin stimulation test only if adrenal insuf \201 ciency is suspected clinically Other tests as clinically indicated Ovarian biopsy \200 Not indicated Annual assessment of women with POI Assess adequacy of sex hormone replacement therapy: \200 Tolerance and compliance \200 Side effects and complications \200 Persistent symp toms of sex hormone de \201 ciency Address fertility issues. Screen for other autoimmune d isease (in autoimmune POI): \200 Clinical evaluation \200 TSH and fasting blood glucose \200 Cosyntropin stimulation test if clinically indicated. Screen for complications: \200 Osteoporosis \200 Cardiovascular disease 50-Draznin-Chap50.indd 261 3/31/2011 2:58:34 PM CHAPTER 50 Premature ovarian insuf \201 ciency (POI) 262 Management Sex hormone replacement therapy Exogenous estrogens (hormone replacement therapy [HT]) are required to alleviate symptoms and prevent the long-term complications of estro- gen de \201 ciency \200\224osteoporosis and possibly cardiovascular disease ( b see Table 50.2). In non-hysterectomized women, a progestagen should be added for 12 \200\22314 days a month to prevent endometrial hyperplasia. Low-dose androgen replacement therapy may improve persistent fatigue and poor libido despite adequate estrogen replacement. Oral contraceptives are an alternative convenient approach to HT in younger women with POI. Fertility A minority of women with POI and a normal karyotype will recover spon- taneously. There is a 5% spontaneous fertility rate. Oocyte donation and in vitro fertilization offer these women their best chance of fertility . Results are promising, with a pregnancy rate of 35% per patient. Results are less good in women with chemotherapy-induced gonadal damage or after pelvic radiotherapy. Ovulation induction therapy has been tried, but the results have been poor. Glucocorticoid therapy has been used in autoimmune POI, but ef \201 - cacy is poor. Table 50.2 Hormone replacement therapy in POI Hormone replacement Dose Estrogen Conjugated estrogens Estradiol valerate Transdermal estradiol 1.25 mg daily 2 \200\2234 mg daily 100 mcg twice a week Progestagen Norethisterone Medroxyprogesterone 12 \200\22314 days a month: 1 mg 10 mg Testosterone IM testosterone Testosterone SC implants 50 \200\223100 mg/month 50 \200\223100 mg every 6 months 50-Draznin-Chap50.indd 262 3/31/2011 2:58:34 PM PROGNOSIS 263 There is currently much research into the removal of functioning ovar- ian tissue in women prior to undergoing cancer chemotherapy followed by its cryopreservation with the aim of re implantation at a later stage when fertility is required. Research into this technique is still in its infancy so if considered, patients and their f amilies must be counseled about the uncertainty of future suc- cess rates associated with o varian cryopreservation. Recent improvements in methods of oocyte cryopreservation using rapid freezing in liquid ni trogen (vitri \201 cation) have allowed women with high chance of POI (e.g., before chemo- or radiotherapy) to store oocytes collected after superovulation. However, this is also ex perimental, and quoted success rates are 20 \200\22330% per patient and depend on age and e gg quality at the time of collection. b See Chapter 51, Menopause, p. 264 \200\223274, for a full review of hor- mone therapy. Prognosis Mortality of women with POI left untreated may be i 2-fold. Estrogen de \201 ciency leads to the following: i Risk of cardiovascular and cerebrovascular disease \200 i Risk of osteoporosis. Up to 2 /3 of women with POI and a normal karyotype have d bone mineral density (BMD), with a z score of \200\2231 or less despite a t least intermittent HT. This may be due to a combination of factors, including an initial delay in initiating HT, poor compliance with HT, and estrogen \200\234underdosing. \200 \235 Further reading Barlow DH (1996). Premature ovarian failure. Bailli \200\231re Clin Obstet Gynecol 10(3):361 \200\223384. Kalantaridou SN, Davis SR, Nelson LM (1998). Premature ovarian failure. Endocrinol Metab Cl in 27(4):989 \200\2231006. Welte, CK (2008). Primary ovarian insuf \201 ciency: a more accurate term for premature ov arian fail- ure. Clin Endocrinol 68:499 \200\223509. 50-Draznin-Chap50.indd 263 3/31/2011 2:58:34 PM CHAPTER 51 Menopause 264 Menopause De \201 nition The menopause is the permanent cessation of menstruation as a result of ova rian failure (see Box 51.1 ) and is a retrospective diagnosis made after 12 months of ameno rrhea. The average age of women at the time of the menopause is 750 years, although smokers reach the menopause 72 years earlier. The perimenopause encompasses the menopause transition and the \201 rst year following the last menstrual period. Box 51.1 Physiology The physiology of the menopause remains poorly understood. Ovaries have a \201 nite numbe r of germ cells, with maximal numbers at 20 weeks of intrauterine life. Thereafter, there i s a gradual reduction in the number of follicles until the perimenopause when there is an e xponential loss of oocytes until the store is depleted at the time of the menopause. Table 51.1 summarizes hormonal changes during the menopausal transition. Inhibin B and anti-M llerian hormone (AMH) are ovarian glycoprotiens produced by follicles as they develop from pre-antral to antral stages. Both may participate in ovarian paracrin e regulation and, with other molecules, regulate the rate of attrition of follicles. Inhibi n B and AMH fall with ovarian aging, before any detectable rise in FSH, and are thus early markers of incipient ovarian failure and onset of perimenopause. In the early perimenopausa l period, FSH levels \202 uctuate, but the grad- ual rise in FSH levels maintains estradi ol production by the ovarian fol- licles. So, contrary to previous belief, average serum es tradiol levels may be high at the onset of the meno-pause transition, falling only toward t he end as the follicles are depleted. 51-Draznin-Chap51.indd 264 4/2/2011 6:50:48 PM 5 1 D r a z n i n C h a p 5 1 . i n d d Table 51.1 Hormonal changes during the menopausal transition 2 6 5 Advanced perimenopause Premenopause (from age 36 years) Early perimenopause Menopause Menstrual cycle Regular, ovulatory Irregular, often short cycles, increasingly anovulatory Oligomenorrhea Amenorrhea Persistently i i i FSH Rising but within normal range Intermittently raised, especially in follicular phase Inhibin B Declining Low Low Very low E2 Normal > Normal Normal/low Low D E F I N T O N I I 4 / 2 2 6 5 / 2 0 1 1 6 : 5 0 : 4 8 P M CHAPTER 51 Menopause 266 Long-term consequences \200 Osteoporosis: During the perimenopausal period there is an ac celerated loss of BMD, with postmenopausal women being more susceptible to osteoporotic fra ctures. Ischemic heart disease (IHD): Postmenopausal women are 2 \200\2233 x more likely to develop IHD than are premenopausal women, even after age adjustments. The menopause is associated with an increase in risk factors for atherosclerosis, including less favorable lipid pro \201 le, d insulin sensitivity, and an i thrombotic tendency. Dementia: Women are 2 \200\2233 x more likely to develop Alzheimer disease than men. It is suggested that estrogen de \201 ciency may play a role in the development of dementia. Clinical presentation There are marked cultural differences in the frequency of symptoms re lated to the menopause. In particular, vasomotor symptoms and mood disturbances are more co mmonly reported in Western countries. Menstrual disturbances (90%) Cycles gradually become increasingly anovulatory and variable in length from about 4 years prior to the menopause. Oligomenorrhea often pre- cedes perman ent amenorrhea. In 10% of women, menses cease abruptly with no preceding transitional perio d. Hot \202 ashes (40%) These are often associated with sweats and skin \202 ushing. They are highly variable and thought to be related to \202 uctuations in estrogen concentra- t ions. They tend to resolve spontaneously within 5 years of menopause. Urinary symptoms (50%) There is atrophy of urethral and bladder mucosa after the menopause and d sensitivity of A-adrenergic receptors of the bladder neck in the perimenopausal perio d. This may result in urinary incontinence and an i risk of urinary tract infections. Sexual dysfunction (40%) Vaginal atrophy may result in dyspareunia and vaginal dryness. Add itionally, falling androgen levels may reduce sexual arousal and libido. Mood changes (25 \200\22350%) Anxiety, memory problems, dif \201 culty in concentration, a nd irritability have all been attributed to the menopause. Women with a history of affec- t ive disorders are at i risk of mood disturbances in the perimenopausal period. 51-Draznin-Chap51.indd 266 4/2/2011 6:50:48 PM EVALUATION (IF HT IS BEING CONSIDERED) 267 Evaluation (if HT is being considered) History \200 Perimenopausal symptoms and their sev erity \200 Assess risk factors for cardiovascular disease and osteoporosis. \200 Assess risk factors for breast cancer and thromboembolic disease. \200 History of active liver disease Examination \200 BP \200 Breasts \200 Pelvic examination, including cervical smear Investigations FSH levels \202 uctuate markedly in the perimenopausal period and correlat e poorly with symptoms. A raised FSH in the perimenopausal period may not necessarily indic ate infertility, so contraception, if desired, should con- tinue until the menopause. Mammography is indicated prior to starting estrogen replacement ther- apy and then following national guidelines. Endometrial biopsy does not need to be performed routinely but is used in women with abnormal uterine bleeding and an abnormal US. 51-Draznin-Chap51.indd 267 4/2/2011 6:50:48 PM CHAPTER 51 Menopause 268 Hormone replacement therapy (HT) The aim of treatment of postmenopausal women is to allevia te meno- pausal symptoms. HT is no longer indicated for the prevention of chronic disease i n postmenopausal women. However, women who have POI should receive HT unless there is an absolute contraindication, until the age of 50 years. Bene \201 ts of HT Hot \202 ashes These respond well to estrogen therapy in a dose-dependent manner. Start w ith a low dose and increase gradually as required to control symp- toms. Higher doses may b e required after hysterectomy, particularly in younger women. For 75% of women, vasomotor symptoms are resolved, so the dose is tapered to the lowest one to control symptoms. The dose of HT should be gradually reduced over weeks, as sudden with drawal of estrogen may precipitate the return of vasomotor symptoms. In women with a contraindication to HT or who are intolerant of it, nonhormonal therapies are available, summarized in Table 51.2. Urinary symptoms A trial of HT, local or systemic, may improve stress and urge incontinence as well as the frequency of cystitis. Table 51.2 Alternatives to HT Symptom Management