Unexplained infertility De \201 nition This is infertility despite normal sexual intercourse occurring at least tw ice weekly, normal semen analysis, documentation of ovulation in several cycles, and normal patent tubes (by laparoscopy). Management From 30 to 50% will become pregnant within 3 years of expectant man- agement. If not pregnant by then, chances that spontaneous pregnancy will occur are greatly reduced an d ART should be considered. In women >34 years of age, expectant management is not an option and up to 6 cycles of intr auterine insemination (IUI), or IVF should be considered. 59-Draznin-Chap59.indd 325 3/31/2011 3:21:26 PM 5 9 D r a z n i n C h a p 5 3 2 6 9 . i n d d 3 Table 59.2 Assisted reproduction techniques (ART) 2 C H A P T E R 6 Technique Indications Pregnancy rates Notes <15% per cycle 15%. Washed and prepared motile spermatozoa are injected into the uterine cavity through a cathe ter just before ovulation Superovulation may improve success rates but is asso- ciated with an increased risk of multiple pregnancy Unexplained infertility mild oligozoospermia (>2 x 10 6 motile sperm) Intrauterine insemination (IUI) (usually offered up to 6 cycles 5 9 I n f e r t i l i t y In vitro fertilization (IVF) Most forms of infertility unless severe male factor 20 \200\22330% pregnancy rate per cycle. After superovulation, ovarian follicles are aspirated under ultrasonic guidance and are fer tilized with prepared sperm in vitro. The embryos are then transferred back into the uterin e cavity, usually 48 hours after insemination. Luteal support using progesterone supplement ation (pessaries or PO) is then provided until pregnancy is con \201 rmed. May adopt a sim ilar technique in women with premature ovarian failure using donated ova which are then fer tilized in vitro with the partner \200\231s sperm. Hormonal support will be required follow ing embryo transfer 80 \200\22390% delivery rate after 6 cycles in women under the age of 35 years. Success rat es markedly reduced after 40 years of age. Babies conceived by IVF have a 2 \227 increased risk of low birth weight and preterm delivery. Gamete intrafallopian transfer (GIFT) Most forms of infertility unless severe male factor. Do not use in women with tubal disease Similar to IVF. Similar to IVF except that retrieved follicles and sperm are injected laparoscopically into a fallopian tube to fertilize naturally. over IVF Intracytoplasmic sperm injection (ICSI) Male infertility. 20 \200\22330% per cycle if female partner is under 40 years of age.There is a small risk o f sex chromosome abnormalities in males (1%) conceived following ICSI Viable spermatozoa are injected directly into oocytes retrieved following superovulation. E mbryos are then implanted into the uterus. Spermatozoa may be concentrated from an ejaculat e or be aspirated from the epididymis or testis in men with obstructive azoospermia. 3 / 3 1 / 2 0 1 1 3 : 2 1 : 2 7 P M MANAGEMENT 327 Results IUI can achieve a pregnancy rate of 15% per cycle, and cumulative delivery rate aft er several cycles is 50%. IVF offers a live birth rate per cycle of >25% in younger women and a cumulative delivery r ate approaching 80%. ICSI allows IVF to be offered in severe oligospermia, with pregnancy r ates equivalent to standard IVF. There is a slight increase in congenital malformations aft er ICSI. A signi \201 cant risk of multiple pregnancy occurs with any form of ART. 59-Draznin-Chap59.indd 327 3/31/2011 3:21:27 PM CHAPTER 59 Infertility 328 Ovulation induction Indications \200 Anovulation due to the following: PCOS \200 Hypopituitarism \200 Hypogonadotropic hypogonadism Controlled ovarian hyperstimulation for ART Pretreatment assessment \200 Exclude thyroid dysfunction and hyperprolactinemia. \200 C heck rubella serology. \200 Con \201 rm normal semen analysis. \200 Con \201 rm tubal patency (laparoscopy, hysterosalpingogram [HSG], or hysterosalping-contrast sonography [Hy CoSy]) prior to gonadotropin use and/or after failed clomifene use. Optimize lifestyle: maintain satisfactory BMI, exercise in moderation, reduce alcohol intake, and stop smoking. Baseline pelvic US is essential to exclude ovarian masses and uterine abnormalities prior to treatment. Clomifene citrate Mode of action \200 Binds to estrogen receptors in hypothalamus, blocking normal negative feedback, thereby i pulse frequency of GnRH. This stimulates FSH and LH release, thereby s timulating the production of one or more dominant ovarian follicles. Antiestrogen effect on endometrium, cervix, and vagina Indications \200 Eugonadotropic anovulation, e.g., PCOS. May also be used in unexplained infertility. It requires normal hypothalamic \200\223pituitary \200\223 ovarian axis to work, thus is ineffective in hypogonadotropic hypogonadism. Contraindications \200 Hepatic dysfunction Administration \200 Start on days 5 of menst rual cycle (may have to induce bleed by giving a progestin for 10 days) and take for a total of 5 days. Dose \200 Start on 50 mg/day and increase by 50 mg every month until midluteal progesterone is >30 nmol/L. Spontaneous ovulation should occur 5 \200\22310 days after the last day of medication. Remain on optimum dose for 6 \200\22312 months. \200 Most patients require 50 \200\223100 mg/day. 59-Draznin-Chap59.indd 328 3/31/2011 3:21:27 PM OVULATION INDUCTION 329 Ideally, follicle growth should be monitored by regular vaginal US to minimize the risk of multiple pregnancies and ovarian hyperstimulation. Ef \201 cacy \200 80 \200\22390% ovulate, with conception rates of 50 \200\22360% in \201 rst 6 ovulatory cycles. Chances of ovulation can be enhanced in nonresponders by admin istration of 10,000 IU of hCG mid-cycle (use US guidance; administer hCG when leading folli cle is at least 20 mm). In overweight women with PCOS who remain anovulatory, the addition of metformin (500 mg tid ) to clomifene may improve ovulation rates. Side effects \200 Hot \202 ashes in 10%, mood swings, depression and headaches in 1%, p elvic pain in 5%, nausea in 2%, breast tenderness in 5%, hair loss in 0.3%, visual disturba nces in 1.5% Ovarian hyperstimulation syndrome (OHSS) in 1% \200 Multiple pregnancies in 7 \200\22310% Risk of ovarian cancer This risk is unknown. Infertility is associated with an i risk of o varian can- cer. Additionally, one study suggests a 2-fold i risk of low-grade ovarian canc er following long-term clomifene use. Further studies are neces- sary, but currently recomm ended maximum treatment duration is 6 \200\22312 months. Tamoxifen Tamoxifen is also an antiestrogen that has similar properties to clomifene. It ca n be used to induce ovulation with results comparable to clomifene. The dose used is 20 \200\22340 mg od for 5 \200\2237 days starting on days 2 \200\2235 of men- strual cycle. Ovarian drilling Laparoscopic ovarian drilling by laser or diathermy in 4 \200\22310 points on the surface of the ovaries may be used in women with PCOS who have failed to conceive o n clomifene. Its ovulation rate of >80% and pregnancy rate of >60% are comparable to gonadotropin therap y, without the risk of multiple pregnancy or ovar- ian hyperstimulation syndrome. It is mos t effective in slim women with PCOS with a high LH. There are few controlled studies, howev er. There is a low risk of pelvic adhesions following ovarian diathermy and a theoretical risk of premature ovarian failure. Gonadotropins Indications \200 Hypogonadotropic hypogonadism \200 Women with PCOS who are clomifene r esistant \200 For superovulation as part of ART 59-Draznin-Chap59.indd 329 3/31/2011 3:21:27 PM CHAPTER 59 Infertility 330 Dose and administration Several regimens are available, all requiring close monitoring with twice- weekly estradiol (E2) measurements and vaginal US. One suggested regime (low-dose s tep-up approach) is as follows: \200 Start at 50 \200\22375 IU/day hMG (or FSH) on days 2 \200\2234 of the menstrual cycle. On day 7 (or 14) of treatment measure serum E2 and perform a vaginal US. If E2 <60 p g/mL and there has been no change in follicle development, then increase hMG (or FSH) by 37 .5 IU. Continue to monitor and increase hMG (or FSH) by 37.5 IU (maximum dose 225 IU/day) o n a weekly basis until there is an ovarian response. If >3 mature follicles (>14 mm) develop or E2 >800 pg/mL, then abandon cycle and restart on half-dose hMG/FSH because of risk of OHSS. \200 Otherwise, give hCG at a dose of 5000 IU to trigger ovulation when follicle is >18 mm in diameter. The dose may be increased to 10,000 IU in the subsequent cycle if ovulation doesn \200\231t occur. Gonadotropins may be used for a total of 6 cycles. If unsuccessful, consider ART. Ef \201 cacy \200 80 \200\22385% pregnancy rate after 6 cycles Side effects \200 Multi ple pregnancy (20%) \200\224OHSS OHSS OHSS is a potentially fatal syndrome of ovarian enlar gement and i vas- cular permeability with accumulation of \202 uid in the peritoneal, ple ural, and pericardial cavities. It occurs during the luteal phase of the cycle, i.e., after hCG stimulation, and is more severe if pregnancy occurs, because of endogenous hCG product ion. Mild OHSS occurs in up to 25% of stimulated cycles and results in abdominal bloating and na usea. It resolves with bed rest and \202 uid replace- ment. Severe OHSS, associated with hypotension, markedly enlarged ovaries, ascites, and pleural and pericardial effusions, occ urs in <0.1%. Women with OHSS need to be hospitalized and resuscitated, as there is i mortality from diss eminated intravascular coagulation and pulmonary emboli. Management should be led by an exp ert reproductive endocrinologist. OHSS is triggered by hCG, so it is best prevented by withholding hCG during at-risk cycles. Risk factors include the presence of multiple ovarian follicles, PCOS, young age, and a pr evious history of OHSS. IVF superovulation This should be accompanied by use of a GnRH agonist starting from the mi d-luteal phase of the preceding cycle (long protocol) or a GnRH antag- onist starting in th e mid-follicular phase of the stimulation cycle (antagon- ist protocol). These strategies p revent premature ovulation before eggs can be collected and signi \201 cantly improve preg nancy rates. GnRH treatment Indications \200 Hypothalamic hypogonadism with normal pituitary function 59-Draznin-Chap59.indd 330 3/31/2011 3:21:27 PM OVULATION INDUCTION 331 Dose and administration \200 Pulsatile GnRH using an infusion pump that is worn continuou sly. This delivers a dose of GnRH every 60 \200\22390 minutes. The dose may be administered either intravenously (2.5 \200\22310 mcg/90 min) or subcutaneously (20 mcg/90 min). Monitoring \200 Monitor E2 levels because of risk of hypoestrogenemia if GnRH is given too frequently. There is little risk of OHSS or multiple pregnancies, so ultrasonic monitoring is not usually necessary. Side effects \200 Allergic reaction Ef \201 cacy \200 Cumulative pregnancy rate of 70 \200\22390% Cryopreservation, fertility, and cancer treatment Chemotherapy and/or radiotherapy for some cancers can adversely affect male and female fertility, resulting in gonadal failure. Male patients should be offered the chance of sperm cryopreservation and storage prior to s tarting cancer treatment so that future fertility may be an option. Cryostorage of oocytes and/or ovarian tissue is less successful. However, it should still b e offered to women of reproductive age about to embark on cancer treatment if they are well enough to undergo ovarian stimula- tion and egg retrieval. They should be counseled about the low chance of a successful pregnancy using such techniques. Storage of frozen embryos is more successful but requires the young female cancer patient t o be in a stable relationship with the potential father of her children. Superovulation/IVF with embryo freezing requires a 3- to 6-week delay in initiation of chemo- or radiotherapy , which must be sanctioned by the lead oncologist. Further reading Braude P, Muhammed S (2003).Assisted conception and the law in the United Kingdom. BMJ 327: 978 \200\223981. Hamilton-Fairley D, Taylor A (2003). Anovulation. BMJ 327:546 \200\223549. Hirsh A (2003). Male subfertility. BMJ 327:669 \200\223672. Royal College of Obstetrics and Gynecology (2004). Fertility assessment and treatment for p eople with fertility problems . pp. 1 \200\223208. 59-Draznin-Chap59.indd 331 3/31/2011 3:21:27 PM CHAPTER 60 Disorders of sexual differentiation 332 Disorders of sexual differentiation Clinical presentation Infancy \200 Ambiguous genitalia ( b evaluation is discussed in Amb iguous genitalia, p. 456) Puberty \200 Failure to progress through puberty (male or female phenotype) \200 Primar y amenorrhea in a female phenotype \200 Virilization of a female phenotype Adulthood \200 Hypogonadism \200 Infertility 60-Draznin-Chap60.indd 332 3/31/2011 3:23:11 PM EVALUATION 333 Evaluation \200 Karyotype 46,XX vs. 46, XY male or female Imaging Look for presence of te stes or ovaries and uterus. Imaging is most easily performed using pelvic US, but MRI may be more sensitive in identify ing internal genitalia and abnormally sited gonads in cryptorchidism. Hormonal evaluation \200 LH/FSH \200 Testosterone, androstenedione, SHBG \200 17 \200 \223hydroxyprogesterone ACTH stimulation (b see Investigations, p. 499) hCG stimulation test ( b see Clinical assessment, p. 295) to assess the presence of functioning testicular material. Measure testosterone, androstenedione, DHT , and SHBG post-stimulation. Others tests, depending on clinical suspicion, e.g., 5-reductase de \201 ciency-check DHT levels before and after hCG stimulation. For causes, b see Box 60.1. 60-Draznin-Chap60.indd 333 3/31/2011 3:23:12 PM CHAPTER 60 Disorders of sexual differentiation 334 Box 60.1 Causes of disorders of sexual differentiation b See also Ambiguous genitalia (p. 4 56). 46,X \200\224 undervirilized male \200 Gonadal differentiation abnormalities, e.g., gonadal dysgenesis Cause unknown in the majority \200 May result from 45,X/46,XY mosaicism or SRY gene mutat ion Leydig cell abnormalities \200 Autosomal recessive \200 Due to inactivating LH receptor gene mutation Biochemical defects of androgen synthesis, e.g.: 3B-HSD, 17 -hydroxylase/17,20-desmolase, or 17B-HSD de \201 ciencies Androgen receptor defects Androgen insensitivity syndrome (p. 335) 5 -reductase de \201 ciency Mutation of 5 -reductase type 2 gene \200 Autosomal recessive inheritance \200 High te stosterone but low DHT concentrations \200 Phenotype can range from female external genit alia to males with hypospadias. Patients characteristically become virilized after puberty. Persistent M llerian duct syndrome M llerian inhibitory substance (MIS), also called anti-M llerian hormone (AMH), or MIS receptor gene mutation True hermaphrodite 46,XX \200\224virilized female \200 Excess fetal androgens \200\224CAH \200 21-OH de \201 ciency (90%) \200 11B-OH de \201 ciency \200 Excess maternal an drogens Drugs \200 Virilizing tumors Placental aromatase de \201 ciency \200 46,XX male Due to a Y-to-X translocation so that the SRY gene is present \200 Phenotype similar to K linefelter \200\231s syndrome True hermaphrodite 60-Draznin-Chap60.indd 334 3/31/2011 3:23:12 PM ANDROGEN INSENSITIVITY SYNDROME 335 Androgen insensitivity syndrome Pathogenesis This syndrome results from a mutation in the androgen receptor gene located on chromosome Xq11 \200\22312. Several mutations may occur, inherited in an X-linked recessiv e fashion. However, approximately 40% of patients have a negative family history. Major gen e deletions result in complete androgen insensitivity, but the more common amino acid subst itutions can result in any of the phenotypes. Incidence is 1:20 000 \200\2231:64 000. Clinical features Complete androgen insensitivity (testicular feminization) results in norm al female external genitalia. However, the vagina is often shorter than nor- mal and may ra rely be absent. No male external sex organs are present, but remnants of M llerian structures are occasion ally present. Testes are usually located in the abdo- men or in the inguinal canal. There i s no spermatogenesis. The syndrome often presents during puberty with primary amenorrhea. Height is above the fem ale average and breast development may be nor- mal. Patients have a normal female habitus b ut little or no pubic and axil- lary hair. Gender identity and psychological development ar e female. Partial androgen insensitivity has a wide phenotypic spectrum, ranging from ambiguous genit alia to a normal male phenotype presenting with infertility. \200 Phenotypic female with mild virilization \200 Reifenstein \200\231s syndrome (undervirilized male with gynecomas tia and hypospadias) \200 Infertile male There is a 9% risk of seminoma. Hormonal evaluation Testosterone levels are in the normal or often above-normal male range. hCG stimulation results in a further rise in testosterone, with little increase in SHBG. Estradiol levels are higher than those in normal males, but lower than the female average. Estrogen is produced by the testes and from periph- eral aromatization of testosterone. LH levels are usually markedly elevated, but FSH is normal. Genetic testing is possible in some centers. Management Orchidectomy is performed to prevent malignancy. Exact timing of surgery is cont roversial but it is usually performed in adolescence after attaining puberty. In phenotypic females with partial androgen insensitivity, gona- dectomy may be performed before puberty to avoid virilization. Estrogen replacement therapy is given in phenotypic females. High-d ose androgen therapy in males with Reifenstein \200\231s syndrome may improve virilization. 60-Draznin-Chap60.indd 335 3/31/2011 3:23:12 PM CHAPTER 60 Disorders of sexual differentiation 336 True hermaphroditism Pathogenesis Pathogenesis is unknown. It may be familial. Affected individuals have both ovarian and testicular tissue, either in the same gonad (ovo testis), or an ovary on one side and a testis on the other. A uterus and a fallopian tube a re usually present, the latter on the side of the ovary or ovotestis. Wolf \201 an structures may be present in a 1/3 of individuals on the side of the testis. The testicular tissue is usually dysgenetic, although the ovarian tissue may be normal. Clinical features Most individuals have ambiguous genitalia and are raised as males, but ju st under 10% have normal female external genitalia. At puberty, 50% of individuals menstruate, which may present as cyclic hematuria in males, and most develop breasts. Feminization and virilization vary widely. Most are infertile, but fertility has been reported. There is a 2% risk of gonadal malignancy, higher in 46,XY individuals. Evaluation \200 46,XX in 70%, 46,XX/46,XY in 20%, and 46,XY in 10% \200 Hypergonadotrop ic hypogonadism is usual. \200 Diagnosis can only be made on gonadal biopsy. 60-Draznin-Chap60.indd 336 3/31/2011 3:23:12 PM GENERAL PRINCIPLES OF MANAGEMENT 337 General principles of management Assignment of gender and reconstructive surgery Virilized females (female pseudohermaphroditism) Most individuals are brought up as females. The timing of feminizing surgery remains controversial but is usually deferred until adoles cence. The decision should be made on an individual basis, by a multidisciplinary specialis t team, the parents and ideally the patient. It appears that a signi \201 cant number of c hildren who have surgery performed during infancy will require further surgery in their tee ns. The results of feminizing genitoplasty, which involves clitoral reduction and vaginoplasty, with regard to sexual function are unclear. Undervirilized males (male pseudohermaphroditism) The decision regarding gender reassignmen t is more complex and depends on the degree of sexual ambiguity in addition to the cause of the disorder and the potential for normal sexual function and fertility. Individuals with complete androgen insensitivity are assigned a female sex, as they are res istant to testosterone therapy, develop female sex- ual characteristics, and have a female gender identity. They may require vaginoplasty in adolescence. Sex assignment of other forms of male pseudohermaphroditism depends on phallic size. Howeve r, the decision should be made by a specialist multi- disciplinary team involving parents w ho should be fully informed. A trial of 3 months of testosterone may be used to enhance phallic growth. Penile reconstruction and orchidopexy by an experienced urologist may be considered in some patients. Testicular prostheses may be required if orchidopexy is not possible. The optima l procedure and timing of surgery remain controversial and the decision should ideally be m ade with the patient when he is old enough to give informed consent. Results of surgery on sexual function are mixed. Gonadectomy There is i risk of gonadoblastoma in most individuals with abdominal tes- tes. Risk is highest in those with dysgenetic gonads and Y chromosome material. Bilateral gonade ctomy should therefore be performed (usually laparascopically). Optimal timing of the gonadectomy is unknown. In androgen insensitivity, the risk of gonado blastoma appears to rise only after the age of 20 years, so orchidectomy is recommended in adolescence after attaining puberty. In most other disorders, gonadectomy prior to puberty is recommended. Early bilateral orchidectomy should also be performed in 46, XY sub- jects with 5 -reducta se de \201 ciency or 17BHSD de \201 ciency who are being raised as females, to prevent vi rilization at puberty. Hormonal therapy Patients with disorders of adrenal biosynthesis, e.g., CAH, require lifelo ng glucocorticoid and usually mineralocorticoid replacement therapy. 60-Draznin-Chap60.indd 337 3/31/2011 3:23:12 PM CHAPTER 60 Disorders of sexual differentiation 338 Most male pseudohermaphrodites and hermaphrodites being raised as males require long-term testosterone replacement therapy. Individuals with 5 -reductase de \201 ciency usually receive supra-physio- logical doses of testosterone to achieve satisfactory DHT levels. Subjects with androgen insensitivity and male pseudohermaphrodites being raised as females should receive estrogen replacement therapy to induce puberty and this should be continued thereafter. Psychological support Disorders relating to sexual identity and function require expert cou nseling. Patient support groups are often helpful. Further reading Creighton S, Minto C (2001). Managing intersex. BMJ 323:1264 \200\2231265. MacLaughin DT, Donahoe PK (2004). Sex determination and differentiation. N Engl J Med 350:3 67 \200\223378. Vogiatzi MG, New MI (1998). Differential diagnosis and therapeutic options for ambiguous ge nitalia. Curr Opin Endocrinol Diabet 5:3 \200\22310. Warne GL, Zajac JD (1998). Disorders of sexual differentiation. Endocrinol Metab Clin North Am 27(4):945 \200\223967. 60-Draznin-Chap60.indd 338 3/31/2011 3:23:12 PM ETIOLOGY 339 Transsexualism De \201 nition Transsexualism is a condition in which an apparently anatomically and gen- etically normal person feels that he or she is a member of the opposite sex. There is an ir reversible discomfort with the anatomical gender, which may be severe, often developing in childhood. Epidemiology \200 More common in males \200 Estimated prevalence of 1:13,000 males and 1:30,000 females Etiology Etiology is unknown and controversial. There is some evidence that it may have a neurobiological basis. There appear to be sex dif ferences in the size and shape of certain nuclei in the hypothalamus. Male-to-female transs exuals have been found to have female differentiation of one of these nuclei, whereas femal e-to-male transsexuals have been found to have a male pattern of differentiation. 61-Draznin-Chap61.indd 339 3/31/2011 3:24:11 PM CHAPTER 61 Transsexualism 340 Management Standards of care A multidisciplinary approach between psychiatrists, endocrinologists, and surgeons is required. The patient should be counseled about treatment options, risks, and implications and realistic expectations discussed. Endocrine disorders should be excluded prior to entry into the gender reassignment program \200\224i.e., ensure normal internal and external genitalia, karyotype, gonadotropins, and testosterone/estradiol. Psychiatric assessment and follow-up is essential before de \201 nitive ther- apy. The tra nssexual identity should be shown to have been persistently present for at least 2 years to ensure a permanent diagnosis. Following this period, the patient should dress and live as a member of the desired sex und er the supervision of a psychiatrist. This should continue for at least 3 \200\2236 months before hormonal treatment and 1 year before surgery. Psychological follow-up and expert cou nseling should be available if required throughout the program, including after surgery. In adolescents, puberty can be reversibly halted by GnRH analog ther- apy, to prevent irrev ersible changes in the wrong gender, until a perman- ent diagnosis is made. Hormonal manipulation For contraindications, b see Box 61.1. Male-to-female transsexuals \200 Suppress male secondary sex characteristics: GnRH analog or high- dose sex steroids Induce female secondary sex characteristics EE2 100 mcg/day or Premarin 1.25 mg or estradiol patch 100 mcg 2 x /week Aims \200 Breast development \200\224maximum after 2 years of treatment. Add progestin short term after maximal estrogen therapy to differentiate ductules, but not need ed long term \200 Development of female fat distribution Box 61.1 Contraindications to hormone manipulation Feminization \200 Prolactinoma \200 Family history of breast cancer \200 Risk of thro mboembolism \200 Active liver disease \200 Cardiovascular or cerebrovascular disease \200 Other contraindication to estrogen therapy (b see p. 268). Masculinization Cardiovascular disease \200 Active liver disease \200 Polycythemia Cerebrovascular disease 61-Draznin-Chap61.indd 340 3/31/2011 3:24:11 PM MANAGEMENT 341 Table 61.1 Maintenance hormone regimens in treatment of transsexualism Masculinization (pre- and post- surgery) Feminization (post-surgery) Testosterone 200 mg IM every 2 weeks Transdermal testosterone (gel or patch) 5 mg od < 40 years OCPs Conjugated estrogens 1.25 mg od > 40 years Conjugated estrogens .625 mg qd Transdermal estradiol .005 \200\2230.1 mg d Body hair and smoother skin. However, facial hair is often resistant to treatment. Muscle bulk and strength \200 Reduction in testicular size \200 Hormonal manipulation h as little effect on the voice. Estrogen \200 Reduce dose of estrogens following gender reassignment surgery and discontinue if possible. However, some subjects will require an antiandrogen to keep es tradiol doses to a minimum (Table 61.1). The dose of estrogen may be halved after gender reassignment surgery (Table 61.1). Change to transdermal estrogens if >40 years old. Change to HT doses once >50 years old. Adjust estrogen dose depending on plasma LH and estradiol levels. Side effects Particularly while on high-dose EE2 therapy: \200 Venous thromboembolism \200 Atherosclerosis \200 Abnormal liver enzymes \200 Depression \200 ?i Risk of bre ast cancer Female-to-male transsexuals The aim is to induce male secondary sex characteristics and sup press female secondary sex characteristics: parenteral testosterone (b see Table 61.1). Aim s \200 Cessation of menstrual bleeding \200 Atrophy of uterus and breasts \200 Increa se muscle bulk and strength \200 Deepening of voice (after 6 \200\22310 weeks) \200 Hir sutism 61-Draznin-Chap61.indd 341 3/31/2011 3:24:11 PM CHAPTER 61 Transsexualism 342 Male body fat distribution \200 Increase in libido Once sexual characteristics are stable (after approximately 1 year of treatment) and follow ing surgery, reduce testosterone dose based on serum testosterone and LH levels. Side effects \200 Acne (in 40%) \200 Weight gain \200 Abnormal liver function \200 Adverse lipid pro \201 le Gender reassignment surgery \200 Performed at least 6 \200\2239 months after starting sex hormone therapy \200 A second psychiatric opinion should be sought prior to referral for surgery. Usually performed in several stages Male-to-female transsexuals \200 Bilateral orchidectomy and resection of the penis \200 Construction of a vagina and labia minora \200 Clitoroplasty \200 Breast augmentation Female to male transsexuals \200 Bilateral mastectomy \200 Hysterectomy and salpingo-oo phorectomy \200 Phalloplasty and testicular prostheses Prognosis \200 There is signi \201 cantly i morbidity in male-to-female transsexuals fro m thromboembolism. The risk of osteoporosis is not thought to be i in transsexuals. Box 61.2 Monitoring of therapy \200 Every 3 months for \201 rst year then every 6 month s \200 Hormonal therapy is lifelong and so patients should be followed up inde \201 nitely. Male to female \200 Physical examination \200 Liver function tests \200 Serum lipids and glucose \200 LH, estradiol, prolactin \200 PSA (>50 years) \200 ?Mammogram (>50 y ears) \200 Bone densitometry Female to male \200 Physical examination \200 Liver function tests \200 Serum lipids and blood glucose \200 LH, testosterone \200 FBC (exclude polycythemia) \200 Bone den sitometry 61-Draznin-Chap61.indd 342 3/31/2011 3:24:12 PM MANAGEMENT 343 There may be a slightly i risk of breast cancer in male-to-female transsexuals. Results from reconstructive surgery, particularly in female-to-male transsexuals, remain suboptimal. There is an i risk of depressive illness and suicide in transsexual individuals. Further reading Gooren LJ, Giltay EJ, Brunck MC (2008). Long-term treatment of transsexuals with cross-sex hor- mones: extensive personal experience. J Clin Endocrinol Metab 93(1):19 \200\22325. Levy A, Crown A, Reid R (2003). Endocrine intervention for transsexuals. Clin Endocrinol 59 :409 \200\223418. Moore E, Wisniewski A, Dobs A (2003) Endocrine treatment of transsexual people: a review of treatment regimens, outcomes and adverse effects. J Clin Endocrinol Metab 88(8):3467 \200 \2233473. Schlatterer K, von Werder K, Stalla GK (1996). Multistep treatment concept of transsexual p atients. Exp Clin Endocrinol Diabet 104:413 \200\223419. 61-Draznin-Chap61.indd 343 3/31/2011 3:24:12 PM This page intentionally left blank Part 5 Endocrine disorders of pregnancy Boris Draznin 62 Thyroid disorders 63 Pituitary disorders 64 Adrenal disorders pregnancy 346 352 361 62-Draznin-Chap62.indd 345 3/31/2011 3:25:36 PM CHAPTER 62 Thyroid disorders 346 Thyroid disorders Normal physiology Effect of pregnancy on thyroid function \200 Iodine stores fall due to i renal clearance and transplacental transfer to fetus. Thyroid size: increase in thyroid volume by 10 \200\22320% due to hCG stimulation and relative iodine de \201 ciency Thyroglobulin: rise corresponds to rise in thyroid size. \200 Thyroid-binding globulin (T BG): 2-fold increase in concentration as a result of reduced hepatic clearance and i synthe sis stimulated by estrogen. Concentration plateaus at 20 weeks \200\231 gestation and falls again postpartum. Total T 4 and T 3 : i concentrations, corresponding to rise in TBG \200 Free T 4 and T 3 : small rise in concentration in \201 rst trimester due to hCG stimulation then fall into normal range. During the second and third trimesters, FT 4 concentration is often just bel ow the normal reference range. Thyroid-stimulating hormone (TSH) is within normal limits in preg- nancy. However, it is suppressed in 13.5% in the \201 rst trimester, 4.5% in the second t rimester, and 1.2% in the third trimester due to hCG thyrotropic effect. There is a positiv e correlation between free T 4 and hCG levels and a negative correlation between TSH and hC G levels in the \201 rst half of pregnancy. Thyrotropin-releasing hormone (TRH) is normal. \200 TSH receptor antibodies: When present in high concentrations in mater- nal serum these may cross the placenta. Antibody titer de creases with progression of the pregnancy. Fetal thyroid function TRH and TSH synthesis occurs by 8 \200\22310 weeks \200\231 gestatio n, and thyroid hor- mone synthesis occurs by 10 \200\22312 weeks \200\231 gestation. TSH, total and freeT 4 and T 3 , and TBG concentrations increase progres- sively throughout gestation. Maternal TSH does not cross the placenta, and although TRH crosses the placenta, it does no t regulate fetal thyroid function. Iodine crosses the placenta and excessive quantities may induce fetal hypothyroidism. Maternal T 4 and T 3 cross the placenta in small quantities a nd are important for fetal brain development in the \201 rst half of gestation. 62-Draznin-Chap62.indd 346 3/31/2011 3:25:37 PM MATERNAL HYPERTHYROIDISM 347 Maternal hyperthyroidism b See Thyrotoxicosis in pregnancy (p. 31). Incidence This condition affects 0.2% of pregnant women. Most patients are diag- nosed befo re pregnancy or in the \201 rst trimester of pregnancy. In women with Graves \200\231 disease in remission, exacerbation may occur in the \201 rst trimester of pregnancy. Graves \200\231 disease The most common scenario is pregnancy in a patient with pre-existin g Graves \200\231 disease on treatment, as fertility is low in patients with untreated thyr otoxicosis. Newly diagnosed Graves \200\231 disease in pregnancy is unusual. Aggravation of disease occurs in the \201 rst trimester with amelioration in second half of pregnancy b ecause of a decrease in maternal immunological activity at that time. Symptoms of thyrotoxicosis are dif \201 cult to differentiate from those of normal pregnan cy. The most sensitive symptoms are weight loss and tachycardia. Goiter is found in most pa tients. Management Risks of uncontrolled hyperthyroidism to mother include heart failure and arryht hmias. Antithyroid drugs (ATDs) are the treatment of choice but cross the placenta. Propylthiourac il is preferred, although the risk of aplasia cutis, a rare fetal scalp defect, with carbim azole is negligible. There is also less transfer to breast milk. Avoid B -blockers, as they may be associated with fetal growth impair- ment with prolonged use. They can be used initially for 2 \200\2233 weeks while antithyroid drugs take affect. Most patients will be on a maintenance dose of an ATD. A high dose of ATD may be necessary initially to achieve euthyroidism as quickly as possible (carbimazole 20 \200\22340 mg/day or propylthiouracil 200 \200\223400 mg/day) in newly diagnosed patients, then the minimal d ose of ATD can be used to maintain euthyroidism. Do not use a block-replace regime, as higher doses of ATDs are required and there is minima l transplacental transfer of T 4 , thereby risking fetal hypothyroidism. Monitor TFTs every 4 \200\2236 weeks. Aim to keep FT 4 at the upper limit of normal and TSH low \200\223normal. In approximately 30% of women, ATDs may be discontinued at 32 \200\223 36 weeks \200\231 gestation. Consider doing this if the patient is euthyroid for at least 4 weeks on the lowest dose of propylthiouracil, but continue to monitor TFTs frequently. Pre sence of a large goiter or ophthalmopathy suggests severe disease; the chances of remission are low, so do not stop the ATD. Risks of neonatal hypothyroidism and goiter are reduced if the woman is on 200 mg propylthi ouracil or less (or carbimazole 20 mg) in the last few weeks of gestation. 62-Draznin-Chap62.indd Sec1:347 3/31/2011 3:25:37 PM CHAPTER 62 Thyroid disorders 348 Propylthiouracil (PTU) is secreted in negligible amounts in breast milk. Carbimazole is sec reted in higher amounts. Breast-feeding is not contrain- dicated if the mother is on <150 m g PTU or 5 mg carbimazole. Give in divided doses after the feeds and monitor neonatal thyro id function. Surgical management of thyrotoxicosis is rarely necessary in pregnancy. The only indication is serious ATD complication (e.g., agranulocytosis) or drug resistance. There is a possibl e i risk of spontaneous abortion or pre- mature delivery associated with surgery during pre gnancy. Radioiodine therapy is contraindicated in pregnancy and for 4 months beforehand. Infants born to mothers with Graves \200\231 disease Risks to fetus of uncontrolled thyroto xicosis \200 i Risk of spontaneous abortion and stillbirth \200 Intrauterine growth res triction (IUGR) \200 Premature labor \200 Fetal or neonatal hyperthyroidism. Follow-up of babies born to mothers on ATDs shows normal weight, height, and intellectual f unction. Fetal hypothyroidism This may occur following treatment of a mother with high doses of ATDs (>200 mg PTU/day), particularly in the latter half of pregnancy. This condi- tion is rare and may be diagnosed by demonstrating a large fetal goiter on fetal US in the presence of f etal bradycardia. Fetal hyperthyroidism This may occur after week 25 of gestation. It results in IUGR, fetal goiter, and tachycardia (fetal heart rate >160 bpm). It may develop if the mother has high titers of TSH-stimulating antibodies (TSAb). Treat by giving the mother an ATD, and monitor fetal heart rate (aim <140 bpm), growth, and goiter size. Neonatal thyrotoxicosis This develops in 1% of infants born to thyrotoxic mothers. It is du e to pla- cental transfer of TSAb. It is transient, usually subsiding by 6 months, but ther e is up to 30% mortality if left untreated. Treat with ATD and B -blockers. Hyperemesis gravidarum (gestational hyperthyroidism) \200 Characterized by severe vomitin g and weight loss. Cause unknown \200 Begins in early pregnancy (week 6 \200\2239 of gest ation) and tends to resolve spontaneously by week 20 of gestation Biochemical hyperthyroidism in two-thirds of affected women, but T 3 is less commonly eleva ted. Mechanism: hCG has TSH-like effect, thus stimulating the thyroid gland and suppressing TSH secretion Degree of thyroid stimulation correlates with severity of vomiting. \200 No other evidenc e of thyroid disease, i.e., no goiter or history of thyroid disease, no ophthalmopathy, and negative thyroid autoanti- bodies Antithyroid drugs are not required and do not improve symptoms of hyperemesis. 62-Draznin-Chap62.indd Sec1:348 3/31/2011 3:25:37 PM MATERNAL HYPOTHYROIDISM 349 Causes of maternal hyperthyroidism \200 Graves \200\231 disease (85% of cases) \200 Tox ic nodule \200 Toxic multinodular goiter \200 Hydatidiform mole Maternal hypothyroidism Prevalence \200 2.5% subclinical hypothyroidism \200 1 \200\223 2% overt hypothyroidism Risks of suboptimal treatment during pregnancy \200 Spontaneous abortion: 2-fold i risk. \200 Pre-eclampsia: 21% of suboptimally treated mothers have pregnancy- induced hypertension (PIH). Also, i risk of anemia during pregnancy and postpartal hemorrhage \200 Risk of impaired f etal intellectual and cognitive development \200 i Risk of perinatal death \200 Other r isks to fetus include those associated with PIH (IUGR, premature delivery, etc). The risk of congenital malformations is not thought to be i .