Part 4 Reproductive endocrinology Margaret E. Wierman 45 Hirsutism 46 Polycystic ovary syndrome (PCOS) 47 Congenital adrenal hyperplasia (CAH) in adults 48 Androgen-secreting tumors 49 Menstrual function disorders 50 Premature ovarian i nsuf \201 ciency (POI) 51 Menopause 52 Oral contraceptive pill (OCP) 53 Testicular physiol ogy 54 Male hypogonadism 55 Androgen therapy 56 Gynecomastia 57 Erectile dysfunction 58 Tes ticular tumors 59 Infertility 60 Disorders of sexual differentiation 61 Transsexualism 222 227 239 249 252 257 264 275 280 284 296 301 306 314 316 332 339 45-Draznin-Chap45.indd 221 3/31/2011 2:46:57 PM CHAPTER 45 Hirsutism 222 Hirsutism De \201 nition Hirsutism (not a diagnosis in itself) is the presence of excess hair growth in females as a result of i androgen production and i skin sensitivity to androgens. b See Table 45.1 for causes. Physiology of hair growth Before puberty, the body is covered with \201 ne, unpigmented v ellus hairs. During adolescence, androgens convert vellus hairs into coarse, pigmented term inal hairs in androgen-dependent areas. The extent of terminal hair growth depends on the c oncentration and duration of androgen exposure as well as on the sensitivity of the individ ual hair follicle. The reason different body regions respond differently to the same androgen concentration is unknown but may be related to the number of androgen receptors in the hair follicle. Genetic factors play an important role in the individual susceptibility to circulating androgens, as evidenced by racial differences in hair growth. Table 45.1 Causes of hirsutism Polycystic ovary syndrome (PCOS) \200 Androgen-secreting tumors \200 Congenital adrenal hyperplasia \200 Cushing \200\231s syndrome \200 Androgen-secreting tumors \200 Acro megaly \200 Severe insulin resistance Ovarian Adrenal 45-Draznin-Chap45.indd 222 3/31/2011 2:46:57 PM ANDROGEN PRODUCTION IN WOMEN 223 Androgen production in women In females, testosterone (T) is secreted primarily by the ovar ies and adrenal glands, although a signi \201 cant amount is produced by the peripheral co nversion of androstenedione and dehydroepiandrosterone (DHEA). Ovarian androgen production is regulated by lutenizing hormone (LH), whereas adrenal production is ACTH dependent. The predominant androgens produced by the ovaries are T and andros- tenedione, and DHEA sul fate (DHEAS) by the adrenal glands. Circulating T is mainly bound to sex hormone binding gl obulin (SHBG) and it is the free T that is biologically active. Testosterone is converted to dihydrotestosterone (DHT) in the skin by the enzyme 5A-reducta se. Androstenedione and DHEA are not signi \201 - cantly protein-bound. See Fig. 45.1. Pituitary HTCA HL Adrenals Ovaries Androstenedione/ DHEAS DHT Testosterone Fig. 45.1 Regulation of androgen production in females. 45-Draznin-Chap45.indd 223 3/31/2011 2:46:57 PM CHAPTER 45 Hirsutism 224 Evaluation Androgen-dependent hirsutism Normally, this develops at puberty. Hairs are coarse and pigme nted and typically grow in a male pattern. It is often accompanied by other evidence of and rogen excess, such as acne, oily skin and hair, and male-pattern alo- pecia. Virilization r efers to severe hirsuitism associated with male pattern balding, anabolic phenotype and cli toromegaly and is associated with very high androgen levels. For signs of virilization, ind icating hyperandrogenism, see Box 45.1. History \200 Age and rate of onset of hirsutism: Slowly progressive hirsutism following puberty suggests a benign cause, whereas rapidly progressive hirsutism of recent onset requires further immediate investigation to rule out an androgen-secreting neoplasm. Menstrual history: ?oligomenorrheic or amenorrhea \200 Presence of other evidence of hype randrogenism , e.g., acne or bitemporal hair recession Drug history: Some progestins used in oral contraceptives may be androgenic (e.g., norethisterone. levonorgestryl). Physical examination Distinguish between androgen-dependent and androgen-independent hair g rowth. Assess the extent and severity of hirsutism. The Ferriman \200\223Gallwey score ( b see Tab le 45.2 ) is used to assess the degree of hair growth in 11 regions of the body. This provi des a semi-objective method of monitoring disease progression and treatment outcome. Virilization should be looked for, as this indicates severe hyperandro- genism and should be further investigated (see Box 45.1 ). Acanthosis nigricans is indicative of insulin resistance of any cause. Rare causes of hyper androgenism, such as Cushing \200\231s syndrome and acromegaly, should be ruled out. Laboratory investigation Serum testosterone should be measured in all females presenting wi th hirsutism. If this is <150 ng/dL the risk of a tumor is low. Further investigations and management of the individual disorders will be discussed in the following chapters. Box 45.1 Signs of virilization \200 Frontal balding \200 Deepening of voice \200 i Mu scle size \200 Clitoromegaly 45-Draznin-Chap45.indd 224 3/31/2011 2:46:58 PM EVALUATION 225 Table 45.2 Assessment of hir-suitism \200\224Ferriman \200\223Gallway score* Site Grade De \201 nition Upper lip 1 2 3 A few hairs at outer margin A small mustache at outer margin A mustache extending halfway f rom outer margin A mustache extending to midline A few scattered hairs Scattered hairs with small concentrations Complete cover, light Complete cover, heavy Circumareolar hairs With midline hair Fusion of these areas Complete cover A few scattered hairs More, but still sca ttered Complete cover, light Complete cover, heavy Sacral tuft of hair Some lateral extensi on Three-quarters cover Complete cover A few midline hairs More than this, still midline Ha lf cover Full cover A few midline hairs A midline streak of hair A midline band of hair An inverted V-shaped growth Sparse growth affecting not more than a fourth of the limb surface More than this, cover still incomplete Complete cover, light Complete cover, heavy Complet e cover of dorsal surface, 2 grades of light and 2 grades of heavy growth As for arm As for arm 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 Chin Chest Upper back Lower back Upper abdomen Lower abdomen Arm 2 3 4 1, 2, 3, 4 Forearm Thigh Leg Total score * Reproduced with permission from Ferriman D, Gallwey JD (1961). Clin ical assessment of body hair growth in women. J Clin Endocrinol and Metab 21(11):1440 \200 \2231447. 1, 2, 3, 4 1, 2, 3, 4 45-Draznin-Chap45.indd 225 3/31/2011 2:46:58 PM CHAPTER 45 Hirsutism 226 Box 45.2 Androgen-independent hair growth Excess vellus hairs are over the face and trunk, including forehead. It does not respond to antiandrogen treatment. Causes of androgen-independent hair growth \200 Drugs, e.g., phenytoin, ciclosporin, gluc ocorticoids \200 Anorexia nervosa \200 Hypothyroidism \200 Familial Further reading Martin KA, Chang JR, Ehrmann DA, et al (2008). Evaluation and treatment of hirsutism in pre- menopausal woman: an Endocrine Society clinical practice guideline. J Cli n Endocrinol Metab 93:1105 \200\2231120. 45-Draznin-Chap45.indd 226 3/31/2011 2:46:58 PM EPIDEMIOLOGY 227 Polycystic ovary syndrome (PCOS) De \201 nition PCOS is a heterogeneous genetic clinical syndrome characterized by hyperand rogenism (both ovarian and/or adrenal), ovulatory dysfunction, and hyperinsulinemia, in whi ch other causes of androgen excess have been excluded ( b see Box 46.1 ). The diagnosis is further supported by the presence of characteristic ovarian morphology on ultrasound (US). Box 46.1 2003 Joint European Society of Human Reproduction and Embryology and American Soci ety of Reproductive Medicine consensus on the diagnosis criteria for PCOS (Rotterdam criter ia) At least two out of three of the following are present: \200 Oligo- or amenorrhea \200 Hyperandrogenism (clinical or biochemical) \200 Polycystic ovaries on US and exclusion of other disorders Epidemiology PCOS is the most common endocrinopathy in women of reproductive age. The estim ated prevalence of PCOS ranges from 5 to 10% on clinical criteria. Polycystic ovaries on US alone are present in 20 \200\22325% of women of reproductive age. 46-Draznin-Chap46.indd 227 3/31/2011 2:47:38 PM CHAPTER 46 Polycystic ovary syndrome (PCOS) 228 Other causes of hyperandrogenic anovulation \200 Congenital adrenal hyperplasia \200 Ac romegaly \200 Cushing \200\231s syndrome \200 Testosterone-secreting tumors \200 Obes ity-induced hyperandrogenic anovulation Pathogenesis The fundamental pathophysiological defect is unknown, but both genetic and env ironmental factors contribute to the disorder. Genetic \200 Familial aggregation of PCOS in 50% of women. A family history of type 2 diabetes mellitus is also more common in women with PCOS. PCOS is probably a polygenic disorder. \200 Insulin synthesis genes, steroid enzyme biosy nthesis genes, and genes involved in reproduction and metabolism are possible candidates, e .g., INS , VNTR , and CYP11 genes; also FTO gene. Hyperandrogenism The main sources of hyperandrogenemia are the ovaries and adrenals. The biochemical basis of ovarian dysfunction is unclear. Studies sug- gest an abnormality o f cytochrome P-450c17 A activity. However, this is unlikely to be the primary event, rather , an index of i steroidogenesis by ovarian theca cells. There is also an increase in the frequency and amplitude of GnRH pulses, resulting in i LH concentrations (high LH/FSH ratio), which is char- acteristic of the syndrome. This may be secondary to anovulation and low progesterone levels. Pituitary \206\221 LH secretion \206\221 Insulin Adrenal \206\221 Androstenedione \206\221 Testosterone \206\221 Androstenedione \206\221 DHEAS Ovary Obesity ?? Hyperinsulinemia Genetic susceptibility \206\223 SHBG \206\221 Free testosterone \206\221 Free estradiol Fig. 46.1 Abnormalities of hormone secretion in PCOS. 46-Draznin-Chap46.indd 228 3/31/2011 2:47:38 PM OTHER CAUSES OF HYPERANDROGENIC ANOVULATION 229 Hyperinsulinemia The overwhelming majority of women with PCOS are insulin resistant. The de fect in insulin sensitivity appears to be selective, mainly affecting the metabolic effects of insulin (effects on muscle and liver) rather than its mitogenic actions (e.g., effects on ovaries). Hyperinsulinemia is further exacerbated by obesity. Women with PCOS have insuf \201 cient B-cell response to a glucose chal- lenge, which is known to be a precursor to type 2 diabetes mellitus. Insulin and IGF-1 receptors are found in abundance in the ovarian stroma, and it has been s hown that insulin, in the presence of LH, stimulates ovarian production of androgens. This is exaggerated in PCOS ovaries. Insulin also inhibits SHBG synthesis by the liver with a consequent rise in free androgen levels. 46-Draznin-Chap46.indd 229 3/31/2011 2:47:39 PM CHAPTER 46 Polycystic ovary syndrome (PCOS) 230 Features \200 Onset of symptoms: Symptoms begin at puberty, often with early menarche. Oligo- and amenorrhea (70%): Due to anovulation. These women are usually well-estrogenized, so there is little risk of osteoporosis, unlike other causes of amenorrhea. Hirsutism (66%) 25% of women also suffer from acne or male-pattern alopecia. Virilization is not a feature of PCOS. There is often a family history of hirsutism or irregular periods. Hirsutism secondary to adrenal or ovarian tumors, in contrast, is usually rapidly progressi ve, associated with virilization and higher testosterone concentrations. Rarely, hirsute women have nonclassical congenital adrenal hyperplasia ( b see Classic presentation, p. 241). This should be excluded, particularly in women with a family history .? Not all CAH women have high T levels Obesity (50%): Symptoms worsen with obesity, as it is accompanied by i testosterone concent rations as a result of the associated hyperinsulinemia. Acanthosis nigricans is common in i nsulin-resistant women with PCOS. Infertility (30%): PCOS accounts for 75% of cases of anovulatory infertility. The risk of spontaneous miscarriage is also thought to be higher than that in the general population Rule out an androgen-secreting tumor If there is the following: \200 Evidence of viriliza tion \200 Testosterone >200 ng/dL \200 Rapidly progressive hirsutism \200 MRI or CT o f adrenals and US of ovaries detecting tumors >1 cm Selective venous sampling has not been shown to be useful in detecting tumors. Risks associated with PCOS Type 2 diabetes mellitus Type 2 diabetes mellitus is 2 \200\2234 x more common in women with PCOS. Impaired glucose tolerance affects 10 \200\22330% of wom en with PCOS, and gestational diabetes is also more prevalent. The prevalence of diabetes mellitus is i in women with PCOS inde- pendent of weight but is highest in the obese group. Dyslipidemia Several studies have shown an i risk of hypercholesterolemia, hypertrig- lycer idemia, and low high-density lipoprotein (HDL) cholesterol in women with PCOS. 46-Draznin-Chap46.indd 230 3/31/2011 2:47:39 PM FEATURES 231 Cardiovascular disease There is evidence that atherosclerosis develops earlier in women wit h PCOS. For example, women with PCOS have been found to be twice as likely to have coronary artery atherosclerosis compared with controls. However, in epidemiological studies, women with PCOS have not been found to have i mortalit y from ischemic heart disease despite their mul- tiple cardiovascular risk factors. No pros pective studies are available. Endometrial hyperplasia and carcinoma In anovulatory women, endometrial stimulation by unop posed estrogen results in endometrial hyperplasia. Several studies have also shown that this results in a 2- to 4-fold excess risk of endometr ial carcinoma in women with PCOS. However, larger prospective studies are required to con \201 rm this excess risk. 46-Draznin-Chap46.indd 231 3/31/2011 2:47:39 PM CHAPTER 46 Polycystic ovary syndrome (PCOS) 232 Laboratory evaluation Selected lab tests are used to con \201 rm the diagnosis, to exclude serious underlying disorders, and to screen for complications. Con \201 rmation of diagnosis Testosterone concentration \200 Performed to con \201 rm biochemical hyperandrogenism and to exclude other causes of hyperandrogenism LH concentration \200 Raised in 50 \200\22370% of anovulatory patients with high LH/FSH r atio. SHBG \200 Low in 50% of women with PCOS owing to the hyperinsulinemic state, with a consequent increase in circulating free androgens Indirect marker of insulin resistance Free androgen index (FAI) This is used as a surrogate for free T levels. FAI = 100 \227 (total testosterone) SHBG Pelvic US of ovaries and endometrium \200 91% sensitivity in experienced hands, with tran svaginal ultrasound giving the highest yield Ultrasonic diagnosis of PCOS is made by the presence of >12 follicular cysts between 2 and 9 mm in diameter or ovarian volume >10 cm 3 . \200 Measurement of endometrial thickness i s also useful in the diagnosis of endometrial hyperplasia in the presence of anovulation. E ndometrial hyperplasia is diagnosed if the endometrial thickness is >10 mm. \200 Transvag inal US will also identify 90% of ovarian virilizing tumors. Exclusion of other disorders Serum prolactin This is used in the presence of infertility or oligoamenorrhea. \200 Mild hyperprolactinemia may be present in up to 30% of women with PCOS, and dopamine agonist tr eatment of this may be necessary if pregnancy is desired. 17 OH (17OHP) progesterone level \200 Used to exclude late-onset congenital adrenal hyper plasia \200 Indicated in those with family history \200 One may also conduct a Cosyntro pin stimulation test looking for an exaggerated rise in 17OHP 30 minutes after ACTH in the presence of nonclassic 21-hydroxylas e de \201 ciency ( b see Clinical presentation, p. 192). 46-Draznin-Chap46.indd 232 3/31/2011 2:47:39 PM LABORATORY EVALUATION 233 If the patient is ovulating, all 17OHP measurements should be taken during the follicular phase of the cycle since androgen levels are higher at midcycle and i n the luteal phase. DHEAS and androstenedione concentrations \200 Both can be moderately raised in PCOS. DHEA S is a useful adrenal marker of hyperandrogenism. In cases of suspected tumors, levels are usually in excess of 8 00 ng/mL. Useful as a marker of adrenal hyperandrogenism Other \200 Depending on clinical suspicion, e.g., 1) urinary free cortisol or overnight dexamethasone suppression test if Cushing \200\231s syndrome is suspected or 2) I GF-1 if acromegaly suspected, but not routinely Screening for complications \200 Serum lipids, blood glucose, and hemoglobin A1C: All wom en with PCOS should have an annual fasting glucose hemoglobin A1C and fasting lipid pro \201 le. All women with PCOS who become pregnant should be screened for gestational diabetes. 46-Draznin-Chap46.indd 233 3/31/2011 2:47:39 PM CHAPTER 46 Polycystic ovary syndrome (PCOS) 234 Management Weight loss Studies have uniformly shown that weight reduction in obese women with PCOS wil l improve insulin sensitivity and signi \201 cantly reduce hyperandro- genemia. Obese wome n are less likely to respond to antiandrogens and infertility treatment. With weight loss, women with PCOS show improvement in hirsutism and restoration of menstrual regularity and fertility. Metformin In obese and lean insulin-resistant women with PCOS, metformin (1 g, 2 \227 dail y) improves insulin sensitivity with a corresponding reduction in serum androgen and LH con centrations and an increase in SHBG levels. Metformin may regulate menstruation by improving ovulatory function and thus inducing ferti lity. Frequency of menstruation may be improved within 3 months of starting therapy. Metfor min does not seem to improve response rates to ovulation induction using clomifene or gonad otropins. Experience of metformin in pregnancy is limited, so it should be dis- continued o nce pregnancy has been con \201 rmed until further data accrue. However, it does not appea r to be teratogenic. The effects of metformin seem to be independent of weight reduction, although the bene \201 ts are greatest in obese women when weight reduction occurs. The effect of metformin o n weight loss remains unclear. There have been few long-term studies looking at the effect of met- formin on hirsutism, bu t it appears that its effects are modest at best, and most women with signi \201 cant hirs utism will require an antiandrogen. Women should be warned of its gastrointestinal (GI) side effects. To minimize these, patien ts should be started on a low dose (500 mg once daily) that may be i gradually to a therape utic dose. A low-fat diet will decrease side effects and improve response. Other insulin sensitizers Troglitazone is a thiazolidinedione, another insulin sensitizer t hat showed encouraging effects on menstruation and hyperinsulinemia in women with PCOS. How ever, it was withdrawn from the market because of liver toxicity. In the future, other thiazolidinediones may be used in the treatment of PCOS, but currently there is insuf \201 cient evidence for their use in PCOS. The thiazolidinediones are asso ciated weight gain and are potentially teratogenic. Their use is therefore not recommended in women seeking fertility. Hirsutism Pharmacological treatment of hirsutism is directed at slowing the growth of new h air but has little impact on established hair. It should be combined with mechanical method s of hair removal, such as electrolysis and laser therapy. Therapy is most effective when s tarted early. 46-Draznin-Chap46.indd 234 3/31/2011 2:47:39 PM MANAGEMENT 235 There is slow improvement over the \201 rst 6 \200\22312 months of treatment. Patients sh ould be warned that facial hair is slow to respond, treatment is prolonged, and symptoms ma y recur after discontinuation of drugs. Adequate contraception is mandatory during pharmacological treat- ment of hirsutism because of possible teratogenicity. Ovarian androgen suppression Oral contraceptive pill (OCP) The estrogen component increases SHBG levels and thus reduces free androgen concentrations; the progestin component inhibit s LH secretion and thus ovarian androgen production. A birth control pill with a nonandrogenic progestin is recommended (norgestryl norgestrel ?or similar progestin). The effect of the OCP alone on hair growth is improved with combin- ation with an antiandrogen. GnRH analogs These suppress gonadotropin secretion and thus ovarian androgen production. They are rarely used. They cause estrogen de \201 ciency so have to be combined with \200 \234add-back \200\235 estrogen treatment. Also, they are expensive and require parenteral a dministration. Use is con \201 ned to women with severe hyperandrogenism in whom antiandrogens have been ineffective or not tolerated. Androgen receptor blockers These are most effective when combined with oral contraceptives. All are contraindicated in pregnancy. They act by competitively inhibiting the binding of testosterone and dihydrotestosterone to the androgen receptor. Spironolactone \200 Antiandrogen of choice \200 Dose: 50 \200\223200 mg/day \200 Side effects: irregular menstrual bleeding if not combined with the OCP. A \201 fth of women complain of GI symptoms when on high doses of spironolactone. Po tassium levels should be monitored if the dose is 100 mg/day or greater, and other potassiu m-sparing drugs should be avoided. E \202 ornithine This agent irreversibly blocks the enzyme ornithine decarboxylase, which is involved in growth of hair follicles. It is administered as a topical cream on the face; its long-term use reduces new hair growt h. Studies have shown its ef \201 cacy in the manage- ment of mild facial hirsutism follow ing at least 8 weeks of treatment. Treatment should be discontinued if there is no bene \201 t at 4 months. It is not a depil atory cream and so must be combined with mechanical methods of hair removal. Side effects include skin irritation with burning or pruritus, acne, hypersensitivity. 46-Draznin-Chap46.indd 235 3/31/2011 2:47:39 PM CHAPTER 46 Polycystic ovary syndrome (PCOS) 236 Amenorrhea A minimum of a withdrawal bleed every 3 months minimizes the risk of endometrial hyperplasia. Treatment \200 OCP with nonandrogenic progestin \200 Desogestrel is a relatively new pr ogesterone-only contraceptive pill with minimal androgenic properties. It may be used to minimize endometrial hyperplasia in amenorrhoeic women with PCOS. Metformin (up to 1 g bid) Alternatives A progestin may be added for the latter half of the cycle. However, there is a risk of exacerbating hirsutism. Less androgenic progestins include medroxyprogesterone, e. g., 5 \200\22310 mg 12 day/month. Infertility Ovulation induction regimens are indicated. Obesity adversely affects fer- tili ty outcome with poorer pregnancy rates and higher rates of miscar- riage, so weight reducti on should be strongly encouraged. Metformin Use remains controversial but probably does not improve ovulation and pregnancy r ates in insulin-resistant, particularly overweight women with PCOS. There are no reported t eratogenic or neonatal complications. \200 Dose: 500 mg od before meals to be i gradually to 1 g bid. If ovulation is restored following 6 months of treatment, then continue for up to 1 year. If pregnancy does not occur, consider other treatments. Side effects: nausea, bloating, diarrhea, vomiting Clomifene citrate This inhibits estrogen negative feedback, i FSH secretion, and thus stimu- lating ovarian follicular growth. \200 Dose: 25 \200\223150 mg/day from days 5 to 9 of menstrual cycle \200 Response rates : 80% of women with PCOS will ovulate, although the pregnancy rate is only 67% and live bir ths are lower. Recent studies have shown that treatment with metformin may improve response to clomifene in resistant cases. Complications: 8% twins, 0.1% higher-order multiple pregnancy. Risk of ovarian neoplasia fo llowing prolonged clomifene treatment remains unclear, so limit treatment to a maximum of 6 cycles. Gonadotropin preparations (human menopausal gonadotropin [hMG] or FSH) These are used in th ose unresponsive to clomifene. Low-dose regimes show better response rates and less complic ations, e.g., 75 IU/day for 2 weeks then increase by 37.5 IU/day every 7 days as required. \200 94% ovulation rate and 40% conception rate after 4 cycles \200 Complications: hype rstimulation, multiple pregnancies \200 Close ultrasonic monitoring is essential. 46-Draznin-Chap46.indd 236 3/31/2011 2:47:39 PM MANAGEMENT 237 Surgery Surgery is particularly effective in slim women with PCOS and high LH concentration s. \200 Complications: surgical adhesions, although usually mild In vitro fertilization ( IVF) \200 In women who fail to respond to ovulation induction \200 60 \200\22380% conce ption rate after 6 cycles Acne Treatment for acne should be started as early as possible to prevent scar- ring. All t reatments take up to 12 weeks before signi \201 cant improvement is seen. All treatments o ther than benzoyl peroxide are contraindicated in pregnancy. Mild to moderate acne Topical benzoyl peroxide 5% has bactericidal properties. It may be us ed in conjunction with oral antibiotic therapy to reduce the risk of developing resistance to antibiotics \200 Side effects: skin irritation and dryness. Add oral antibiotics if no improvement is seen after 2 months of treatment. Moderate to severe acne Topical retinoids, e.g., tretinoin, isotretinoin, are useful alone in mild acne or in conjunction with antibiotics in moderately severe acne. Continue as main tenance therapy to prevent further acne outbreaks. \200 Side effects: irritation, photose nsitivity. Apply high factor sunscreen before sun exposure. Avoid in acne involving large a reas of skin. Oral antibiotics, e.g., tetracycline 500 mg bid, doxycycline 100 mg od, or minocycline 100 mg OD can also be used. Response is usually seen by 6 weeks and full ef \201 cacy by 3 mon ths. Continue antibiotics for 2 months after control is achieved. Prescription is usually g iven for a 3- to 6-month course. Continue topical retinoids and/or benzoyl peroxide to prev ent further outbreaks. Spironolactone and birth control pills containing nonandrogenic pro- gestins will improve acne. Severe acne Isotretinoin is very effective in women with severe acne or acne that has not r esponded to other oral or topical treatments. Used early it can min- imize scarring in in \202 ammatory acne. However, it is highly toxic and can only be prescribed by a dermatologi st. Further reading Dunaif A (1997). Insulin resistance and polycystic ovary syndrome: mechanis m and implications for pathogenesis. Endocr Rev 18(6):774 \200\223800. Ehrmann DA (2005). Polycystic ovary syndrome. N Engl J Med 352:1223 \200\2231236. Ehrmann DA, Rychlik D (2003). Pharmacological treatment of polycystic ovary syndrome. Semin Reprod Med 21(3):277 \200\223283. 46-Draznin-Chap46.indd 237 3/31/2011 2:47:39 PM CHAPTER 46 Polycystic ovary syndrome (PCOS) 238 Ledger WL, Clark T (2003). Long-term consequences of polycystic ovary syndrome. Royal Colle ge of Obsterics and Gynecology Guideline number 33. 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 synd rome. Clin Endocrinol 60(1):1 \200\22317. 46-Draznin-Chap46.indd 238 3/31/2011 2:47:39 PM PATHOGENESIS 239 Congenital adrenal hyperplasia (CAH) in adults De \201 nition CAH is an inherited group of disorders characterized by a de \201 ciency o f one of the enzymes necessary for cortisol biosynthesis. More than 90% of cases are due to 21A-hydroxylase de \201 ciency. There is a wide clinical spectrum, from presentation in the neonatal period with salt wasting and virilization to nonclassic CAH in adulthood. CAH is inherited in an autosomal recessive manner. Epidemiology \200 Wide racial variations, most common in those of Jewish origin \200 Ca rrier frequency of classic CAH: 1:60 in white people \200 Carrier frequency of nonclassic CAH: 19% in Ashkenazi Jews, 13.5% in Hispanics, 6% in Italians, and 3% in other Caucasian populations Pathogenesis Genetics CYP21 encodes for the 21A-hydroxylase enzyme, located on the short ar m of chromosome 6 (chromosome 6p21.3). In close proximity is the CYP21 pseudogene, with 90% homology but no functional activity. 21A-Hydroxylase de \201 ciency results from gene mutations, partial gene deletions, or gen e conversions in which sequences from the pseudogene are transferred to the active gene, re ndering it inactive. There is a correlation between the severity of the molecular defect and the clinical severi ty of the disorder. Nonclassic CAH is usually due to a point mutation (single base change); missense mutations result in simple virilizing disease, whereas a gene conversion or parti al deletion usually results in presentation in infancy with salt wasting or severe viriliza tion. 47-Draznin-Chap47.indd 239 4/1/2011 5:34:03 PM CHAPTER 47 Congenital adrenal hyperplasia 240 Biochemistry b See Fig. 47.1. 21A-Hydroxylase de \201 ciency results in aldosterone and cortisol de \201 - ciency. Ther e is ACTH oversecretion because of the loss of negative feedback, and this causes adrenocor tical hyperplasia and excessive accu- mulation of 17-hydroxy progesterone (17OHP) and other steroid precur- sors. These are then shunted into androgen synthesis pathways, resulting i n testosterone and androstenedione excess. Cholesterol 17 OH 17 OH Pregnenolone 3 HSD Dehydroepiandrosterone 17 HSD 17OH Pregnenolone Aromatase Progesterone HO12 17OH Progesterone Androstenedione Testosterone Estradiol HO12 11-Deoxycortisol 11 OH Deoxycorticosterone 11 OH Corticosterone Cortisol 18-OH Corticosterone Aldosterone Fig. 47.1 Adrenal steroid biosynthesis pathway. 47-Draznin-Chap47.indd 240 4/1/2011 5:34:03 PM CLINICAL PRESENTATION 241 Clinical presentation Classic CAH Most patients are diagnosed in infancy; their clinical presentation is dis- cus sed elsewhere ( b see Congenital adrenal hyperplasia, p. 239). Problems persisting into adulthood include sexual dysfunction and sub- fertility in women, particularly in salt wasters. Reconstructive genital sur- gery is required in the majority of women who were virilized at birth to create an adequate vaginal introitus. With improvem ent of medical and surgical care, pregnancy rates have improved. Fertility rates of 60 \200 \22380% have been reported in women with classic CAH. In men, high levels of adrenal androgens suppress gonadotropins and thus testicular functio n. Spermatogenesis may therefore be affected if CAH is poorly controlled. Suboptimally controlled CAH in men also predisposes them to devel- oping testicular adrenal rests. These are always benign but may be misdi- agnosed as testicular tumors. 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.