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Amenorrhoea
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Seminar
Amenorrhoea David T Baird The occurrence of regular monthly periods in women of reproductive age is the most obvious manifestation of cyclical ovarian activity. A reduction in the frequency of menses (oligomenorrhoea) or complete cessation for more than 6 months (amenorrhoea) is usually a sign of a disturbance in the pattern of secretion of ovarian hormones. It is only in the past 100 years, as the average family size has declined, that the majority of women have experienced monthly periods for a substantial proportion of their lives.1 Previously most women were amenorrhoeic during childhood, pregnancy, lactation, and after the menopause. These physiological causes of amenorrhoea all have their pathological equivalents, and the disturbance in the pattern of menstruation is in many cases the presenting symptom of underlying disease. Secondary amenorrhoea refers to absence of menses in women who previously have had spontaneous periods. In primary amenorrhoea, menses have never occurred by the time of expected menarche (up to 16 years). Management and treatment are dependent on an accurate diagnosis of the cause.
Causes Anatomical Amenorrhoea can be due to defects or absence of the uterus or vagina (anatomical) or, more commonly, to a lack of stimulation of the uterus by ovarian hormones (endocrine).2 The presence of any bleeding, even if very infrequent, indicates the presence of a uterus and excludes a local genital cause. Absence of the uterus is associated with several developmental abnormalities that present as primary amenorrhoea, including congenital absence of the uterus and testicular feminisation (androgen resistance) syndrome. The latter disorder can be caused by several mutations of the androgen receptor, which result in a lack of androgenisation during sexual differentiation and, hence, a female phenotype.3 However, the secretion of Müllerian-duct inhibitory hormone by the testes is normal, hence (as in normal male fetuses) the development of the uterus and upper vagina is inhibited. Another anatomical cause of primary amenorrhoea is obstruction of the outflow from the genital tract owing to an imperforate hymen or transverse vaginal septum presenting as apparently delayed menarche in girls with normal sexual development and cyclical pelvic pain.4 Destruction of the uterine cavity by infection (pelvic tuberculosis), endometrial resection, or as a complication of over-vigorous curettage of the uterus (Asherman’s syndrome) will result in secondary amenorrhoea.5 Endocrine Because normal functioning of the ovaries depends on a tightly controlled feedback system involving the anterior Lancet 1997; 350: 275–79 Department of Obstetrics and Gynaecology, Centre for Reproductive Biology, University of Edinburgh, Edinburgh EH3 9EW, UK (Prof D T Baird FRCOG)
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Causes of amenorrhoea Physiological Prepuberty, pregnancy, lactation, postmenopause Pathological Local genital causes Congenital—eg, testicular feminisation Acquired—eg, Asherman’s syndrome Hyopthalamic Congenital—eg, Kallmann’s syndrome Acquired—eg, weight loss, craniopharyngioma Pituitary Tumour—eg, prolactinoma Infarction—eg, Sheehan’s syndrome Ovarian Congenital—eg, gonadotropin-receptor defect, resistant ovary syndrome Acquired—eg, radiation
pituitary and hypothalamus, a functional or structural defect in any one component will lead to a breakdown in cyclical ovarian activity and, hence, disturbance in the pattern of menstruation (panel, figure 1). Kallmann’s syndrome is a congential disorder resulting in failure of pubertal development in both men and women.6 This syndrome is characterised by a failure of the secretion of normal amounts of gonadotropin-releasing hormone (GnRH) into the hypothalamic-hypophyseal portal blood. Kallmann’s syndrome is due, in many cases, to a mutation in the gene situated on the p.22.3 region of the X chromosome, coding for adhesion-molecule-like/X chromosome (AD-MLX).7 This 679-aminoacid protein has homology to fibronectin and has a role in facilitating the migration during fetal life of GnRH neurons from the nasal pit to the hypothalamus. Various other associated abnormalities, such as anosmia and synkinesia (mirror movements), are present to a variable degree. In affected adults, the olfactory sulci are extremely hypoplastic.8 Other structural causes of hypogonadotropism include trauma, severe head injury, craniopharyngioma, pituitary adenomas, and infarction of the anterior pituitary (Sheehan’s syndrome). Functional defects in hypothalamic function are a quite common cause of amenorrhoea; they can result from weight loss, anorexia nervosa, excessive exercise, debilitating diseases, or psychological stress. The common feature is a reduction in the activity of the GnRH neurons in the hypothalamus, leading to a corresponding reduction in secretion of follicle-stimulating hormone (FSH) and luteinising hormone (LH). In normal women during the follicular phase of the cycle, LH is secreted from the pituitary in pulses approximately once an hour in response to hourly bursts of activity of GnRH neurons.9 If LH pulses occur less frequently than every 2 hours, normal follicular development and ovulation do not occur.10 The changes represent a continuum ranging from a hypogonadotropic state resembling childhood, as in anorexia nervosa, through to minor abnormalities in ovarian cycles, such as insufficient corpus luteum. 275
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identified in some women with this condition, although most cases remain unexplained.13 The block to folliculogenesis in many cases appears, however, to be in the recruitment from primordial follicles to primary follicles, a step that is independent of gonadotropins. There may be some genetic defect in the growth factors (eg, GDF9) that normally regulate recruitment of primordial follicles.14
Investigation and diagnosis Successful management of women with amenorrhoea depends on an accurate diagnosis.2 On the basis of a careful clinical history and examination and some relatively simple investigations, a diagnosis of sufficient accuracy to permit appropriate treatment can be made for the vast majority of cases. Clinical examination should concentrate on the signs of secondary sexual characteristics (eg, breast development). Pelvic ultrasound examination may be helpful in identifying the presence of uterus and ovaries. At the initial consultation blood should be taken for the measurement of FSH, LH, prolactin, and oestradiol. The measurement of thyrotropin and thyroxine can be reserved for women with clinical signs of thyroid disease, and serum testosterone for those with hirsutism or androgenisation. On the basis of these initial investigations, women with amenorrhoea can be classified into four groups and any further investigations should be reserved for specific indications (figure 2). It is important to remember that the commonest cause of secondary amenorrhoea is pregnancy, which should always be excluded before any further investigations are undertaken. Figure 1: Hypothalamic-pituitary-ovarian-uteric axis GnRH=gonadotropin-releasing hormone; FSH=follicle-stimulating hormone; LH=luteinising hormone.
Amenorrhoea can have primary ovarian causes. Unlike the testes, an ovary devoid of gametes cannot produce normal amounts of steroid hormones. Gonadal dysgenesis occurs in association with several chromosomal abnormalities, the commonest of which is 45X0 monosomy (Turner’s syndrome). As in the absence of a gonad (gonadal agenesis) the Müllerian duct structures differentiate normally and, hence, the adult phenotype is female. These women who present with primary amenorrhoea are found to have “streak” gonads, derived from either testis or ovary, and a male or female karyotype. Secondary ovarian failure with high concentrations of gonadotropins can occur at any stage of reproductive life and is due to premature depletion of primordial oocytes. The formation of oocytes is completed by the 5th month of intrauterine life. In normal women, there is continuous depletion of primordial follicles until the stock is exhausted at the menopause (age 40–55 years). The causes of premature ovarian failure are largely unknown, but some cases occur in association with autoimmune disorders such as Addison’s disease, minor chromosomal abnormalities, and galactosaemia.11 An increasingly common cause of premature ovarian failure is treatment with radiation or cytotoxic drugs (eg, cyclophosphamide) for malignant disease (eg, Hodgkin’s lymphoma, Wilm’s tumour, breast cancer), which causes complete destruction or partial depletion of the stock of oocytes. Rarely, ovarian failure (ie, hypergonadotropic hypogonadism) may be due to resistant ovary syndrome.12 In this disorder the ovaries contain many primordial follicles, which are apparently resistant to the action of gonadotropins. Mutations in the FSH receptor have been 11
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Management The appropriate managment depends not only on the diagnosis but also on the presenting problem. The treatment for a woman who wishes to become pregnant may be quite different from that for a woman who simply requires correction of her hypo-oestrogenic state.
Hypergonadotropic hypogonadism This disorder is perhaps one of the easiest to identify, although elucidation of the underlying aetiology may be much more difficult. If the concentration of FSH is in the castrate range (>30 IU/L) and the concentration of oestradiol is below 60 pmol/L, the diagnosis of ovarian failure or (rarely) resistant ovary syndrome is certain. If the amenorrhoea is primary, analysis of karyotype will identify women with testicular dysgenesis, in whom the residual gonadal tissue should be removed because of the risk of malignant disorder.15 Replacement therapy with oestrogen will induce secondary sexual characteristics in girls with primary amenorrhoea and in combination with cyclical progestogens will prevent the consequences of chronic hypo-oestrogenism (osteoporosis and cardiovascular disease) in women of reproductive age. Although fertility cannot be restored because the loss of oocytes is irreversible, women with ovarian failure can become pregnant after appropriate hormonal replacement therapy and transfer to the uterus of embryos from donors. Hyperprolactinaemia The concentration of prolactin is above the normal range (which is up to about 500 mU/L) in 20% of women with secondary amenorrhoea. If hypothyroidism is excluded by
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Figure 2: Investigation of women with amenorrhoea
measurement of thyrotropin concentration and there is no history of ingestion of drugs (eg, phenothiazines) that might have caused the hyperprolactinaemia, pituitary disease is likely. Modern techniques of pituitary imaging such as magnetic resonance imaging will identify a pituitary adenoma (prolactinoma) in more than 50% of such women.16 Other pituitary tumours, such as growthhormone-secreting tumours and null cell adenomas, may be associated with hyperprolactinaemia, probably through interference with the hypothalamic-hypophyseal portal system. Treatment with dopamine agonists (eg, bromocriptine, cabergoline, quinagolide) leads to reduction in prolactin secretion and inhibition of tumour growth in most women with tumour-related hyperprolactinaemia.17 Ovulation and fertility usually return within a few months, so contraception will be required for women who do not wish to become pregnant. In theory, the combined oral contraceptive pill should be avoided because oestrogen can stimulate the secretion of prolactin; however, in practice, when oral contraceptives are given with dopamine agonists, there is little risk of causing enlargement of a prolactinoma. During normal pregnancy there is slight enlargement of the anterior pituitary associated with the increased secretion of prolactin. Women with prolactinomas should be advised to defer conception for some months after starting treatment with dopamine agonists, so that some shrinkage of the tumour can be achieved. In some women with large tumours that are causing symptoms of pressure on adjacent structures (eg, optic nerves), which are not relieved by treatment with dopamine agonists, surgical resection will be necessary. Some centres offer transphenoidal resection of the tumour as initial treatment.18 Although most women are cured after surgical treatment, a minority remain hyperprolactinaemic and require subsequent medical treatment. Since the pregnancy rate after treatment with dopamine agonists is very high, most centres reserve surgical treatment for women who are unresponsive to or intolerant of medical management or in whom there are persistent signs of pressure on structures surrounding the pituitary.
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Hypogonadotropic hypogonadism Reduction in the secretion of LH and FSH results in failure of follicular development and, hence, a lack of secretion of oestradiol by the ovaries. If this sequence of events occurs before puberty, there will be primary amenorrhoea and a lack of development of secondary sexual characteristics. Failure of the hypothalamus is commoner than that of the pituitary; causes include Kallmann’s syndrome, craniopharyngioma, and infiltrative diseases such as sarcoidosis. In the majority of women with hypogonadotropic hypogonadism, no organic disease can be identified in the hypothalamus or anterior pituitary. A functional cessation of the activity of the hypothalamic neurons that release GnRH is associated with weight loss, psychological stress, or debilitating disease. Because GnRH secretion is very low, the concentrations of LH, FSH, and oestradiol are also very low. The degree of weight loss that results in secondary amenorrhoea varies from a few kilograms in an adolescent who is “dieting” to a reduction of up to 50% of bodyweight in classic anorexia nervosa.19 In the latter condition, secondary changes in metabolism occur as a result of chronic imbalance between intake and expenditure of energy, and treatment is therefore extremely difficult. The chronic hypo-oestrogenic state can have serious long-term consequences—eg, premature osteoporosis and cardiovascular disease. Management of hypothalamic amenorrhoea associated with weight loss must focus primarily on trying to correct the underlying cause of energy deficit. Anorexia nervosa is potentially fatal and requires prompt diagnosis and treatment in a specialist unit. Advice about diet and amount of exercise may be sufficient to correct the energy imbalance and restore ovarian function in many women with weight-related amenorrhoea. However, if amenorrhoea persists for more than 12 months, some form of oestrogen replacement should be considered, to prevent the long-term consequences of hypooestrogenism. Cyclical ovarian activity, ovulation, and fertility can be restored in women with hypothalamic amenorrhoea by administration of GnRH.10,20 This treatment requires 277
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injection of pulses of GnRH every 1–2 hours by means of a portable programmable pump to simulate pulsatile secretion of endogenous GnRH. In women who are underweight, attempts to induce ovulation should be deferred until near-normal body-mass index has been reached because, if conception occurred, the growth of the fetus might otherwise be compromised.21 Treatment with pulsatile GnRH is very successful, with 90% of women becoming pregnant after six cycles and a low rate of multiple pregnancies.22 Unlike women with hypothalamic dysfunction or disease, women with anovulation due to pituitary disease (eg, Sheehan’s syndrome) do not respond to GnRH and require treatment with gonadotropins. These hormones were, up to a few years ago, prepared from the urine of postmenopausal women and contained variable amounts of FSH and LH and large amounts of urinary impurities.23 Pure FSH and LH have now been prepared by recombinant DNA technology and should provide a more reliable source.24 The therapeutic aim of stimulating the development of a single ovulatory follicle is very difficult to achieve because the treatment over-rides the feedback system that controls the secretion of FSH and LH in the normal cycle. Even with careful monitoring by serial measurement of hormones and of follicle growth by ultrasound in specialist centres, the proportion of multiple pregnancies is rarely below 25%.
Normogonadotropic anovulation About 30% of women with secondary amenorrhoea have concentrations of gonadotropins within the normal range. Careful analysis of the pattern of LH secretion may reveal subtle abnormalities such as frequent high-amplitude pulses, as in polycystic ovary syndrome, or failure of an LH surge.25 Many women with these disorders present with irregularities in the pattern of menstrual bleeding (dysfunctional uterine bleeding) rather than secondary amenorrhoea. Follicular development and oestrogen production continue but are arrested at some stage short of full maturation of an ovulatory follicle. Thus, these women although anovulatory show no signs of oestrogen deficiency. Rather, as a result of the continued exposure to oestrogen unopposed by progesterone, the endometrium may become hyperplastic. References 1 2
3
4
5 6 7
8
9
Short RV. The evolution of human reproduction. Proc R Soc Lond 1976; 195: 3–24. Baird DT. Amenorrhea, anovulation and dysfunctional uterine bleeding. In: De Groot LJ, ed. Endocrinology, 3rd edn. New York: WB Saunders, 1995: 2059–79. Imperato-McGinley J. Male pseudohermaphroditism. In: Adashi EY, Rock JA, Rosenwalks Z, eds. Reproductive endocrinology, surgery and technology, vol 1. Philadelphia: Lippincott-Raven, 1995: 935–55. Rock JA. Congenital outflow tract obstruction. In: Adashi EY, Rock JA, Rosenwalks Z, eds. Reproductive endocrinology, surgery and technology. Philadelphia: Lippincott-Raven, 1995: 1445–74. Schenker JG, Margalioth E. Intrauterine adhesions: an updated appraisal. Fertil Steril 1992; 37: 593–610. Kallmann F, Schonfield WA, Barrera SE. The genetic aspects of primary eunuchoidism. Am J Mental Defic 1994; 48: 203–36. Schwanzel-Fukuda M, Bick D, Pfaff DN. Luteinising-hormonereleasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. Mol Brain Res 1989; 6: 311–26. Takeda T, Takasu N,Yamauchi K, et al. MRI imaging of the hypoplasia of the rhinencephalon in a patient with Kallmann’s syndrome. Intern Med 1992; 31: 394–96. Ferin M, Jenelenicz R, Warren M. The menstrual cycle. New York: Oxford University Press, 1993.
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Polycystic ovaries are associated in the majority of women with normogonadotropic anovulation.26 Characteristically, the ovaries are enlarged because the stroma is hyperplastic. Scattered around the periphery of the cortex are many small antral follicles, which do not develop beyond about 5–10 mm in diameter. The polycystic ovary syndrome describes the association of polycystic ovaries with obesity, hirsutism, anovulation, and irregular bleeding. However, the ultrasound appearances of polycystic ovaries occur in some women with regular ovulatory cycles and have been reported in 20% of normal women.27 Pedigree studies have shown that inheritance is linked to premature baldness in men,28 although attempts to identify an association of the syndrome with mutations in the steroid metabolism gene CYP17 have not been confirmed.29 Many women with polycystic ovary syndrome are hyperinsulinaemic and show other features of syndrome X.30 It seems unlikely, therefore, that this syndrome is due to a single gene defect—rather it is likely to be the end result of several abnormalities that result in arrest of follicle development. Antioestrogens (clomiphene and tamoxifen) induce ovulation and restore fertility in most women in this group. The rise in FSH concentration that occurs during a short 5day course (eg, 50 mg clomiphene daily from day 3 to day 7) is sufficient to promote further development of small antral follicles, which subsequently ovulate. For women who do not respond to antioestrogens, FSH may be needed. Women with polycystic ovaries are notoriously sensitive to gonadotropins, but a high rate of single ovulations has been reported with use of very low daily doses.29
Conclusion Amenorrhoea is a symptom not a diagnosis. Comprehensive history and clinical examination in conjunction with a few carefully chosen investigations are sufficient to make an acurate diagnosis in the vast majority of cases. Successful management depends not only on identification of the underlying cause, but also on the needs and concerns of the individual woman. The absence of menses in itself has no deleterious effect on health, but amenorrheoa may be a presenting symptom of an underlying disorder (eg, pituitary tumour or hypooestrogenism) that requires treatment. 10 Leyendecker G, Wildt L. Induction of ovulation with chronic intermittent (pulsatile) administration of GnRH in women with hypothalamic amenorrhoea. J Reprod Fertil 1983; 69: 397–409. 11 Taylor AE, Schneyer AL, Sluss PM, Crowley WF Jr. Ovarian failure, resistance and activation. In: Adashi EY, Leung PCK, eds. The ovary. New York: Raven Press, 1993: 629–61. 12 Wentz AC. Resistant ovary syndrome. In: Adashi EY, Rock JA, Rosenwalks Z, eds. Reproductive endocrinology, surgery and technology, vol 2. Philadelphia: Lippincott-Raven, 1995: 1385–92. 13 Huhtaniemi I, Pakarinen P, Nilsson C, Pettersson K, Tapanainen J, Aittomäki K. Polymorphisms and mutations of gonadotropin and gonadotropin receptor genes. In: Filicori M, Flamigni C, eds. The ovary: regulation, dysfunction and treatment. Amsterdam: Elsevier Science, 1996: 89–101. 14 Dong J, Albertini DF, Nishimori K, Kamur TR, Lu N, Matzu MM. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 1996; 383: 531–35. 15 Troche V, Hernandez E. Neoplasia arising in dysgenetic gonads. Obstet Gynecol Surv 1986; 41: 74–79. 16 Blackwell RE. Hyperprolactinaemia: evaluation and management. Endocrinol Metab Clin North Am 1992; 21: 105–25. 17 Ferrari C, Crosignani PG. Medical treatment of hyperprolactinaemic disorders. Hum Reprod 1986; 1: 507–14. 18 Laws ER Jr. Pituitary surgery. Endocrinol Metab Clin North Am 1987; 16: 647–65.
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THE LANCET 19 Warren MP. Anorexia nervosa. In: de Groot LJ, ed. Endocrinology, 3rd edn. New York: WB Saunders, 1993: 2679–91. 20 Filicori M, Flamigni C, Meriggiola ML, et al. Endocrine response determines the clinical outcome of pulsatile gonadotropin-releasing hormone induction in different disorders. J Clin Endocrinol Metab 1991; 72: 965–72. 21 Van der Spuy ZM, Steer PJ, McCusker M, Steele SJ, Jacobs HS. Outcome of pregnancy in underweight women after spontaneous and induced ovulation. BMJ 1988; 296: 962–65. 22 Homburg R, Eshel E, Armar NA, et al. One hundred pregnancies after treatment with pulsatile luteinising hormone releasing hormone to induce ovulation. BMJ 1989; 298: 809–12. 23 Baird DT. Ovulation induction: current status and future prospects of gonadotropin therapy. In: Adashi EY, Leung PCK, eds. The ovary. New York: Raven, 1993: 529–44. 24 Loumaye E, Campbell R, Salat-Baroux J. Human follicle-stimulating hormone produced by recombinant DNA technology: a review for
clinicians. Hum Reprod Update 1995; 1: 188–99. 25 Yen SSC. The polycystic ovary syndrome. Clin Endocrinol 1980; 12: 177–207. 26 Fox R, Corrigan E, Thomas PA, Hull MGR. The diagnosis of polycystic ovaries in women with oligo-amenorrhoea: predictive power of endocrine tests. Clin Endocrinol 1991; 34: 127–31. 27 Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. BMJ 1986; 293: 355–59. 28 Ferriman D, Purdie AW. The inheritance of polycystic ovary disease and a possible relationship to premature balding. Clin Endocrinol 1979; 11: 291. 29 Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333: 853–61. 30 Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin dependent diabetes mellitus. Am J Med 1995; 98: 335–95.
Further reading
Molitch ME, Elton RL, Blackwell RE, et al. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicentre study. J Clin Endocrinol Metab 1985; 60: 698–705. Serri O, Rasio E, Beauregard M, Hary J, Somma M. Recurrence of hyperprolactinemia after selective transphenoidal adenectomy in women with prolactinoma. N Engl J Med 1983; 309: 280–83. Webster J, Piscitelli G, Poli A, Ferrari CI, Ismail I, Scanlon MF. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinaemic amenorrhea. N Engl J Med 1994; 331: 904–09.
Physiology Baird DT. The ovarian cycle. In: Hillier SG, ed. Ovarian endocrinology. Oxford: Blackwell Science, 1991: 1–24. Clarke IJ. GnRH and ovarian hormone feedback. Oxf Rev Reprod Biol 1987; 9: 54–95. Corner GW. Our knowledge of the menstrual cycle, 1910–1950. Lancet 1951; i: 919. Crowley WF Jr, Filicori M, Spratt DI, Santoro NF. The physiology of gonadotropin releasing hormone (GnRH) secretion in men and women. Recent Prog Horm Res 1985; 41: 473–525. Harris GW, Naftolin I. Hypothalamus and control of ovulation. Br Med Bull 1970; 26: 3–9. Hotchkiss J, Knobil E. The hypothalamic pulse generator: the reproductive core. In: Adashi EY, Rock JA, Rosenwalks Z, eds. Reproductive endocrinology, surgery and technology. Philadelphia: Lippincott Raven, 1995: 123–62.
Anatomical causes March CM. Acquired intrauterine adhesions: Asherman’s syndrome. In: Adasi EY, Rock JA, Rozenwalks Z, eds. Reproductive endocrinology, surgery and technology, vol 2. Philadelphia: Lippincott-Raven, 1995: 1475–88.
Hypergonadotropic hypogonadism Bardin CW, Bullock LP, Sherins RJ, et al. Androgen metabolism and mechanisms of action in male pseudohermaphroditism: a study of testicular feminization. Recent Prog Horm Res 1973; 29: 65–109. French FS, Lubahn DB, Brown TR, et al. Molecular basis of androgen insensitivity. Recent Prog Horm Res 1990; 46: 1–42. Jones SG, de Moraes-Ruehsen M. A new syndrome of amenorrhoea in association with hypergonadotropism and apparently normal ovarian follicular apparatus. Am J Obstet Gynecol 1969; 104: 597–600. Lutjen P, Trouson A, Leeton J, Findlay J, Wood C, Revoir P. The establishment and maintenance of pregnancy using in vitro fertilization and embryo donation in a patient with primary ovarian failure. Nature 1984; 307: 174–75. Muller J, Schwartz M, Skakkebaek NE. Analysis of the sex-determining region of the Y chromosome (SRY) in sex reversed patients: point mutation in SRY causing sex reversion in a 46XY female. J Clin Endocrinol Metab 1992; 75: 331–33. Rabinowe SL, George KL, Ravnikar VA, Dluhy RG, Dib SA. Premature menopause: monoclonal antibody defined T lymphocyte abnormalities and antiovarian antibodies. Fertil Steril 1989; 51: 450–59. Saenger P. Turner’s syndrome. N Engl J Med 1996; 335: 1749–54. Sohval AR. The syndrome of pure gonadal dysgenesis. Am J Med 1965; 38: 615–25. Starup J, Sele V, Henricksen B. Amenorrhoea associated with increased production of gonadotropins and a morphologically normal ovarian follicular apparatus. Acta Endocrinol (Copenh) 1971; 66: 248–56.
Hyperprolactinaemia Bohnet HG, Dahlen HG, Wuttke W, Schneider HPG. Hyperprolactinemic anovulatory syndrome. J Clin Endocrinol Metab 1976; 42: 132–43. Crosignani PG, Ferrari C. Dopaminergic treatments for hyperprolactinaemia. Baillière’s Clin Obstet Gynaecol 1990; 4: 441–55. Forbes AP, Hennemann PH, Griswold GC, Albright F. Syndrome characterized by galactorrhea, amenorrhea and low urinary FSH: comparison with acromegaly and normal lactation. J Clin Endocrinol Metab 1954; 14: 265–71. Gemzell C, Wang CF. Outcome of pregnancy in women with pituitary adenoma. Fertil Steril 1979; 31: 363–72. Gindoff PF, Loucopoulas A, Jewelewicz R. Treatment of hyperprolactinemic amenorrhea with pulsatile gonadotropin-releasing hormone therapy. Fertil Steril 1986; 46: 1156–61.
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Hypogonadotropic hypogonadism Berga SL, Mortola JF, Girton L, Suh B, Lauchlin GA, Pham P, Yen SSC. Neuroendocrine observations in women with functional hypothalamic amenorrhoea. J Clin Endocrinol Metab 1989; 68: 301–08. Lachelin GCL, Yen SSC. Hypothalamic chronic anovulation. Am J Obstet Gynecol 1978; 130: 825–31. Letterie GS, Coddington CC, Collins RL, Merriam GR. Ovulation induction using s.c. pulsatile gonadotrophin-releasing hormone: effectiveness at different pulse frequencies. Hum Reprod 1996; 11: 19–22. Sheehan HL. Simmond’s disease due to postpartum necrosis of the anterior pituitary. Q J Med 1939; 8: 277–309. Wildt L, Leyendecker G. Induction of ovulation by the chronic administration of naltrexone in hypothalamic amenorrhoea. J Clin Endocrinol Metab 1987; 64: 1334–35.
Normogonadotropic anovulation Adashi EY. Clomiphene citrate-induced ovulation. Semin Reprod Endocrinol 1986; 4: 255–76. Carey AH, Chan KL, Short F, White DM, Williamson R, Franks S. Evidence for a single gene effect in polycystic ovaries and male pattern baldness. Clin Endocrinol 1993; 38: 653–58. Carey AH, Waterworth D, Patel K, et al. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP 17. Hum Mol Genet 1994; 3: 1873–76. Fauser BCJM. Step-down follicle-stimulating hormone regimens in polycystic ovary syndrome. In: Filicori M, Flamigni C, eds. Ovulation induction: basic science and clinical advances. Amsterdam: Excerpta Medica, 1994: 145–52. Franks S. Polycystic ovary syndrome: a changing perspective. Clin Endocrinol 1989; 31: 87–120. Gharani N, Waterworth DM, Batty S, et al. Association of the steroid metabolising gene CYP 11␣ with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet 1997; 6: 397–402. Glasier AF. Clomiphene citrate. Baillière’s Clin Obstet Gynaecol 1990; 4: 491–501. Hague WM, Adams J, Reeders ST, Peto TE, Jacobs HS. Familial polycystic ovaries: a genetic disease? Clin Endocrinol 1988; 29: 593–605. Kazer RR, Kessel B, Yen SSC. Circulating luteinizing hormone pulse frequency in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1987; 65: 233–36. Kiddy DS, Sharp PS, White DM, et al. Difference in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: an analysis of 263 consecutive cases. Clin Endocrinol 1990; 32: 213–20. Polson DW, Kiddy D, Mason HD, Franks S. Induction of ovulation with clomiphene citrate in women with polycystic ovary syndrome: the difference between responders and non-responders. Fertil Steril 1989; 51: 30–34. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935; 29: 181–91. White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab 1996; 81: 3821–24.
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Seminar
Amenorrhoea David T Baird The occurrence of regular monthly periods in women of reproductive age is the most obvious manifestation of cyclical ovarian activity. A reduction in the frequency of menses (oligomenorrhoea) or complete cessation for more than 6 months (amenorrhoea) is usually a sign of a disturbance in the pattern of secretion of ovarian hormones. It is only in the past 100 years, as the average family size has declined, that the majority of women have experienced monthly periods for a substantial proportion of their lives.1 Previously most women were amenorrhoeic during childhood, pregnancy, lactation, and after the menopause. These physiological causes of amenorrhoea all have their pathological equivalents, and the disturbance in the pattern of menstruation is in many cases the presenting symptom of underlying disease. Secondary amenorrhoea refers to absence of menses in women who previously have had spontaneous periods. In primary amenorrhoea, menses have never occurred by the time of expected menarche (up to 16 years). Management and treatment are dependent on an accurate diagnosis of the cause.
Causes Anatomical Amenorrhoea can be due to defects or absence of the uterus or vagina (anatomical) or, more commonly, to a lack of stimulation of the uterus by ovarian hormones (endocrine).2 The presence of any bleeding, even if very infrequent, indicates the presence of a uterus and excludes a local genital cause. Absence of the uterus is associated with several developmental abnormalities that present as primary amenorrhoea, including congenital absence of the uterus and testicular feminisation (androgen resistance) syndrome. The latter disorder can be caused by several mutations of the androgen receptor, which result in a lack of androgenisation during sexual differentiation and, hence, a female phenotype.3 However, the secretion of Müllerian-duct inhibitory hormone by the testes is normal, hence (as in normal male fetuses) the development of the uterus and upper vagina is inhibited. Another anatomical cause of primary amenorrhoea is obstruction of the outflow from the genital tract owing to an imperforate hymen or transverse vaginal septum presenting as apparently delayed menarche in girls with normal sexual development and cyclical pelvic pain.4 Destruction of the uterine cavity by infection (pelvic tuberculosis), endometrial resection, or as a complication of over-vigorous curettage of the uterus (Asherman’s syndrome) will result in secondary amenorrhoea.5 Endocrine Because normal functioning of the ovaries depends on a tightly controlled feedback system involving the anterior Lancet 1997; 350: 275–79 Department of Obstetrics and Gynaecology, Centre for Reproductive Biology, University of Edinburgh, Edinburgh EH3 9EW, UK (Prof D T Baird FRCOG)
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Causes of amenorrhoea Physiological Prepuberty, pregnancy, lactation, postmenopause Pathological Local genital causes Congenital—eg, testicular feminisation Acquired—eg, Asherman’s syndrome Hyopthalamic Congenital—eg, Kallmann’s syndrome Acquired—eg, weight loss, craniopharyngioma Pituitary Tumour—eg, prolactinoma Infarction—eg, Sheehan’s syndrome Ovarian Congenital—eg, gonadotropin-receptor defect, resistant ovary syndrome Acquired—eg, radiation
pituitary and hypothalamus, a functional or structural defect in any one component will lead to a breakdown in cyclical ovarian activity and, hence, disturbance in the pattern of menstruation (panel, figure 1). Kallmann’s syndrome is a congential disorder resulting in failure of pubertal development in both men and women.6 This syndrome is characterised by a failure of the secretion of normal amounts of gonadotropin-releasing hormone (GnRH) into the hypothalamic-hypophyseal portal blood. Kallmann’s syndrome is due, in many cases, to a mutation in the gene situated on the p.22.3 region of the X chromosome, coding for adhesion-molecule-like/X chromosome (AD-MLX).7 This 679-aminoacid protein has homology to fibronectin and has a role in facilitating the migration during fetal life of GnRH neurons from the nasal pit to the hypothalamus. Various other associated abnormalities, such as anosmia and synkinesia (mirror movements), are present to a variable degree. In affected adults, the olfactory sulci are extremely hypoplastic.8 Other structural causes of hypogonadotropism include trauma, severe head injury, craniopharyngioma, pituitary adenomas, and infarction of the anterior pituitary (Sheehan’s syndrome). Functional defects in hypothalamic function are a quite common cause of amenorrhoea; they can result from weight loss, anorexia nervosa, excessive exercise, debilitating diseases, or psychological stress. The common feature is a reduction in the activity of the GnRH neurons in the hypothalamus, leading to a corresponding reduction in secretion of follicle-stimulating hormone (FSH) and luteinising hormone (LH). In normal women during the follicular phase of the cycle, LH is secreted from the pituitary in pulses approximately once an hour in response to hourly bursts of activity of GnRH neurons.9 If LH pulses occur less frequently than every 2 hours, normal follicular development and ovulation do not occur.10 The changes represent a continuum ranging from a hypogonadotropic state resembling childhood, as in anorexia nervosa, through to minor abnormalities in ovarian cycles, such as insufficient corpus luteum. 275
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identified in some women with this condition, although most cases remain unexplained.13 The block to folliculogenesis in many cases appears, however, to be in the recruitment from primordial follicles to primary follicles, a step that is independent of gonadotropins. There may be some genetic defect in the growth factors (eg, GDF9) that normally regulate recruitment of primordial follicles.14
Investigation and diagnosis Successful management of women with amenorrhoea depends on an accurate diagnosis.2 On the basis of a careful clinical history and examination and some relatively simple investigations, a diagnosis of sufficient accuracy to permit appropriate treatment can be made for the vast majority of cases. Clinical examination should concentrate on the signs of secondary sexual characteristics (eg, breast development). Pelvic ultrasound examination may be helpful in identifying the presence of uterus and ovaries. At the initial consultation blood should be taken for the measurement of FSH, LH, prolactin, and oestradiol. The measurement of thyrotropin and thyroxine can be reserved for women with clinical signs of thyroid disease, and serum testosterone for those with hirsutism or androgenisation. On the basis of these initial investigations, women with amenorrhoea can be classified into four groups and any further investigations should be reserved for specific indications (figure 2). It is important to remember that the commonest cause of secondary amenorrhoea is pregnancy, which should always be excluded before any further investigations are undertaken. Figure 1: Hypothalamic-pituitary-ovarian-uteric axis GnRH=gonadotropin-releasing hormone; FSH=follicle-stimulating hormone; LH=luteinising hormone.
Amenorrhoea can have primary ovarian causes. Unlike the testes, an ovary devoid of gametes cannot produce normal amounts of steroid hormones. Gonadal dysgenesis occurs in association with several chromosomal abnormalities, the commonest of which is 45X0 monosomy (Turner’s syndrome). As in the absence of a gonad (gonadal agenesis) the Müllerian duct structures differentiate normally and, hence, the adult phenotype is female. These women who present with primary amenorrhoea are found to have “streak” gonads, derived from either testis or ovary, and a male or female karyotype. Secondary ovarian failure with high concentrations of gonadotropins can occur at any stage of reproductive life and is due to premature depletion of primordial oocytes. The formation of oocytes is completed by the 5th month of intrauterine life. In normal women, there is continuous depletion of primordial follicles until the stock is exhausted at the menopause (age 40–55 years). The causes of premature ovarian failure are largely unknown, but some cases occur in association with autoimmune disorders such as Addison’s disease, minor chromosomal abnormalities, and galactosaemia.11 An increasingly common cause of premature ovarian failure is treatment with radiation or cytotoxic drugs (eg, cyclophosphamide) for malignant disease (eg, Hodgkin’s lymphoma, Wilm’s tumour, breast cancer), which causes complete destruction or partial depletion of the stock of oocytes. Rarely, ovarian failure (ie, hypergonadotropic hypogonadism) may be due to resistant ovary syndrome.12 In this disorder the ovaries contain many primordial follicles, which are apparently resistant to the action of gonadotropins. Mutations in the FSH receptor have been 11
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Management The appropriate managment depends not only on the diagnosis but also on the presenting problem. The treatment for a woman who wishes to become pregnant may be quite different from that for a woman who simply requires correction of her hypo-oestrogenic state.
Hypergonadotropic hypogonadism This disorder is perhaps one of the easiest to identify, although elucidation of the underlying aetiology may be much more difficult. If the concentration of FSH is in the castrate range (>30 IU/L) and the concentration of oestradiol is below 60 pmol/L, the diagnosis of ovarian failure or (rarely) resistant ovary syndrome is certain. If the amenorrhoea is primary, analysis of karyotype will identify women with testicular dysgenesis, in whom the residual gonadal tissue should be removed because of the risk of malignant disorder.15 Replacement therapy with oestrogen will induce secondary sexual characteristics in girls with primary amenorrhoea and in combination with cyclical progestogens will prevent the consequences of chronic hypo-oestrogenism (osteoporosis and cardiovascular disease) in women of reproductive age. Although fertility cannot be restored because the loss of oocytes is irreversible, women with ovarian failure can become pregnant after appropriate hormonal replacement therapy and transfer to the uterus of embryos from donors. Hyperprolactinaemia The concentration of prolactin is above the normal range (which is up to about 500 mU/L) in 20% of women with secondary amenorrhoea. If hypothyroidism is excluded by
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Figure 2: Investigation of women with amenorrhoea
measurement of thyrotropin concentration and there is no history of ingestion of drugs (eg, phenothiazines) that might have caused the hyperprolactinaemia, pituitary disease is likely. Modern techniques of pituitary imaging such as magnetic resonance imaging will identify a pituitary adenoma (prolactinoma) in more than 50% of such women.16 Other pituitary tumours, such as growthhormone-secreting tumours and null cell adenomas, may be associated with hyperprolactinaemia, probably through interference with the hypothalamic-hypophyseal portal system. Treatment with dopamine agonists (eg, bromocriptine, cabergoline, quinagolide) leads to reduction in prolactin secretion and inhibition of tumour growth in most women with tumour-related hyperprolactinaemia.17 Ovulation and fertility usually return within a few months, so contraception will be required for women who do not wish to become pregnant. In theory, the combined oral contraceptive pill should be avoided because oestrogen can stimulate the secretion of prolactin; however, in practice, when oral contraceptives are given with dopamine agonists, there is little risk of causing enlargement of a prolactinoma. During normal pregnancy there is slight enlargement of the anterior pituitary associated with the increased secretion of prolactin. Women with prolactinomas should be advised to defer conception for some months after starting treatment with dopamine agonists, so that some shrinkage of the tumour can be achieved. In some women with large tumours that are causing symptoms of pressure on adjacent structures (eg, optic nerves), which are not relieved by treatment with dopamine agonists, surgical resection will be necessary. Some centres offer transphenoidal resection of the tumour as initial treatment.18 Although most women are cured after surgical treatment, a minority remain hyperprolactinaemic and require subsequent medical treatment. Since the pregnancy rate after treatment with dopamine agonists is very high, most centres reserve surgical treatment for women who are unresponsive to or intolerant of medical management or in whom there are persistent signs of pressure on structures surrounding the pituitary.
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Hypogonadotropic hypogonadism Reduction in the secretion of LH and FSH results in failure of follicular development and, hence, a lack of secretion of oestradiol by the ovaries. If this sequence of events occurs before puberty, there will be primary amenorrhoea and a lack of development of secondary sexual characteristics. Failure of the hypothalamus is commoner than that of the pituitary; causes include Kallmann’s syndrome, craniopharyngioma, and infiltrative diseases such as sarcoidosis. In the majority of women with hypogonadotropic hypogonadism, no organic disease can be identified in the hypothalamus or anterior pituitary. A functional cessation of the activity of the hypothalamic neurons that release GnRH is associated with weight loss, psychological stress, or debilitating disease. Because GnRH secretion is very low, the concentrations of LH, FSH, and oestradiol are also very low. The degree of weight loss that results in secondary amenorrhoea varies from a few kilograms in an adolescent who is “dieting” to a reduction of up to 50% of bodyweight in classic anorexia nervosa.19 In the latter condition, secondary changes in metabolism occur as a result of chronic imbalance between intake and expenditure of energy, and treatment is therefore extremely difficult. The chronic hypo-oestrogenic state can have serious long-term consequences—eg, premature osteoporosis and cardiovascular disease. Management of hypothalamic amenorrhoea associated with weight loss must focus primarily on trying to correct the underlying cause of energy deficit. Anorexia nervosa is potentially fatal and requires prompt diagnosis and treatment in a specialist unit. Advice about diet and amount of exercise may be sufficient to correct the energy imbalance and restore ovarian function in many women with weight-related amenorrhoea. However, if amenorrhoea persists for more than 12 months, some form of oestrogen replacement should be considered, to prevent the long-term consequences of hypooestrogenism. Cyclical ovarian activity, ovulation, and fertility can be restored in women with hypothalamic amenorrhoea by administration of GnRH.10,20 This treatment requires 277
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injection of pulses of GnRH every 1–2 hours by means of a portable programmable pump to simulate pulsatile secretion of endogenous GnRH. In women who are underweight, attempts to induce ovulation should be deferred until near-normal body-mass index has been reached because, if conception occurred, the growth of the fetus might otherwise be compromised.21 Treatment with pulsatile GnRH is very successful, with 90% of women becoming pregnant after six cycles and a low rate of multiple pregnancies.22 Unlike women with hypothalamic dysfunction or disease, women with anovulation due to pituitary disease (eg, Sheehan’s syndrome) do not respond to GnRH and require treatment with gonadotropins. These hormones were, up to a few years ago, prepared from the urine of postmenopausal women and contained variable amounts of FSH and LH and large amounts of urinary impurities.23 Pure FSH and LH have now been prepared by recombinant DNA technology and should provide a more reliable source.24 The therapeutic aim of stimulating the development of a single ovulatory follicle is very difficult to achieve because the treatment over-rides the feedback system that controls the secretion of FSH and LH in the normal cycle. Even with careful monitoring by serial measurement of hormones and of follicle growth by ultrasound in specialist centres, the proportion of multiple pregnancies is rarely below 25%.
Normogonadotropic anovulation About 30% of women with secondary amenorrhoea have concentrations of gonadotropins within the normal range. Careful analysis of the pattern of LH secretion may reveal subtle abnormalities such as frequent high-amplitude pulses, as in polycystic ovary syndrome, or failure of an LH surge.25 Many women with these disorders present with irregularities in the pattern of menstrual bleeding (dysfunctional uterine bleeding) rather than secondary amenorrhoea. Follicular development and oestrogen production continue but are arrested at some stage short of full maturation of an ovulatory follicle. Thus, these women although anovulatory show no signs of oestrogen deficiency. Rather, as a result of the continued exposure to oestrogen unopposed by progesterone, the endometrium may become hyperplastic. References 1 2
3
4
5 6 7
8
9
Short RV. The evolution of human reproduction. Proc R Soc Lond 1976; 195: 3–24. Baird DT. Amenorrhea, anovulation and dysfunctional uterine bleeding. In: De Groot LJ, ed. Endocrinology, 3rd edn. New York: WB Saunders, 1995: 2059–79. Imperato-McGinley J. Male pseudohermaphroditism. In: Adashi EY, Rock JA, Rosenwalks Z, eds. Reproductive endocrinology, surgery and technology, vol 1. Philadelphia: Lippincott-Raven, 1995: 935–55. Rock JA. Congenital outflow tract obstruction. In: Adashi EY, Rock JA, Rosenwalks Z, eds. Reproductive endocrinology, surgery and technology. Philadelphia: Lippincott-Raven, 1995: 1445–74. Schenker JG, Margalioth E. Intrauterine adhesions: an updated appraisal. Fertil Steril 1992; 37: 593–610. Kallmann F, Schonfield WA, Barrera SE. The genetic aspects of primary eunuchoidism. Am J Mental Defic 1994; 48: 203–36. Schwanzel-Fukuda M, Bick D, Pfaff DN. Luteinising-hormonereleasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. Mol Brain Res 1989; 6: 311–26. Takeda T, Takasu N,Yamauchi K, et al. MRI imaging of the hypoplasia of the rhinencephalon in a patient with Kallmann’s syndrome. Intern Med 1992; 31: 394–96. Ferin M, Jenelenicz R, Warren M. The menstrual cycle. New York: Oxford University Press, 1993.
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Polycystic ovaries are associated in the majority of women with normogonadotropic anovulation.26 Characteristically, the ovaries are enlarged because the stroma is hyperplastic. Scattered around the periphery of the cortex are many small antral follicles, which do not develop beyond about 5–10 mm in diameter. The polycystic ovary syndrome describes the association of polycystic ovaries with obesity, hirsutism, anovulation, and irregular bleeding. However, the ultrasound appearances of polycystic ovaries occur in some women with regular ovulatory cycles and have been reported in 20% of normal women.27 Pedigree studies have shown that inheritance is linked to premature baldness in men,28 although attempts to identify an association of the syndrome with mutations in the steroid metabolism gene CYP17 have not been confirmed.29 Many women with polycystic ovary syndrome are hyperinsulinaemic and show other features of syndrome X.30 It seems unlikely, therefore, that this syndrome is due to a single gene defect—rather it is likely to be the end result of several abnormalities that result in arrest of follicle development. Antioestrogens (clomiphene and tamoxifen) induce ovulation and restore fertility in most women in this group. The rise in FSH concentration that occurs during a short 5day course (eg, 50 mg clomiphene daily from day 3 to day 7) is sufficient to promote further development of small antral follicles, which subsequently ovulate. For women who do not respond to antioestrogens, FSH may be needed. Women with polycystic ovaries are notoriously sensitive to gonadotropins, but a high rate of single ovulations has been reported with use of very low daily doses.29
Conclusion Amenorrhoea is a symptom not a diagnosis. Comprehensive history and clinical examination in conjunction with a few carefully chosen investigations are sufficient to make an acurate diagnosis in the vast majority of cases. Successful management depends not only on identification of the underlying cause, but also on the needs and concerns of the individual woman. The absence of menses in itself has no deleterious effect on health, but amenorrheoa may be a presenting symptom of an underlying disorder (eg, pituitary tumour or hypooestrogenism) that requires treatment. 10 Leyendecker G, Wildt L. Induction of ovulation with chronic intermittent (pulsatile) administration of GnRH in women with hypothalamic amenorrhoea. J Reprod Fertil 1983; 69: 397–409. 11 Taylor AE, Schneyer AL, Sluss PM, Crowley WF Jr. Ovarian failure, resistance and activation. In: Adashi EY, Leung PCK, eds. The ovary. New York: Raven Press, 1993: 629–61. 12 Wentz AC. Resistant ovary syndrome. In: Adashi EY, Rock JA, Rosenwalks Z, eds. Reproductive endocrinology, surgery and technology, vol 2. Philadelphia: Lippincott-Raven, 1995: 1385–92. 13 Huhtaniemi I, Pakarinen P, Nilsson C, Pettersson K, Tapanainen J, Aittomäki K. Polymorphisms and mutations of gonadotropin and gonadotropin receptor genes. In: Filicori M, Flamigni C, eds. The ovary: regulation, dysfunction and treatment. Amsterdam: Elsevier Science, 1996: 89–101. 14 Dong J, Albertini DF, Nishimori K, Kamur TR, Lu N, Matzu MM. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 1996; 383: 531–35. 15 Troche V, Hernandez E. Neoplasia arising in dysgenetic gonads. Obstet Gynecol Surv 1986; 41: 74–79. 16 Blackwell RE. Hyperprolactinaemia: evaluation and management. Endocrinol Metab Clin North Am 1992; 21: 105–25. 17 Ferrari C, Crosignani PG. Medical treatment of hyperprolactinaemic disorders. Hum Reprod 1986; 1: 507–14. 18 Laws ER Jr. Pituitary surgery. Endocrinol Metab Clin North Am 1987; 16: 647–65.
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THE LANCET 19 Warren MP. Anorexia nervosa. In: de Groot LJ, ed. Endocrinology, 3rd edn. New York: WB Saunders, 1993: 2679–91. 20 Filicori M, Flamigni C, Meriggiola ML, et al. Endocrine response determines the clinical outcome of pulsatile gonadotropin-releasing hormone induction in different disorders. J Clin Endocrinol Metab 1991; 72: 965–72. 21 Van der Spuy ZM, Steer PJ, McCusker M, Steele SJ, Jacobs HS. Outcome of pregnancy in underweight women after spontaneous and induced ovulation. BMJ 1988; 296: 962–65. 22 Homburg R, Eshel E, Armar NA, et al. One hundred pregnancies after treatment with pulsatile luteinising hormone releasing hormone to induce ovulation. BMJ 1989; 298: 809–12. 23 Baird DT. Ovulation induction: current status and future prospects of gonadotropin therapy. In: Adashi EY, Leung PCK, eds. The ovary. New York: Raven, 1993: 529–44. 24 Loumaye E, Campbell R, Salat-Baroux J. Human follicle-stimulating hormone produced by recombinant DNA technology: a review for
clinicians. Hum Reprod Update 1995; 1: 188–99. 25 Yen SSC. The polycystic ovary syndrome. Clin Endocrinol 1980; 12: 177–207. 26 Fox R, Corrigan E, Thomas PA, Hull MGR. The diagnosis of polycystic ovaries in women with oligo-amenorrhoea: predictive power of endocrine tests. Clin Endocrinol 1991; 34: 127–31. 27 Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. BMJ 1986; 293: 355–59. 28 Ferriman D, Purdie AW. The inheritance of polycystic ovary disease and a possible relationship to premature balding. Clin Endocrinol 1979; 11: 291. 29 Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333: 853–61. 30 Dunaif A. Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin dependent diabetes mellitus. Am J Med 1995; 98: 335–95.
Further reading
Molitch ME, Elton RL, Blackwell RE, et al. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicentre study. J Clin Endocrinol Metab 1985; 60: 698–705. Serri O, Rasio E, Beauregard M, Hary J, Somma M. Recurrence of hyperprolactinemia after selective transphenoidal adenectomy in women with prolactinoma. N Engl J Med 1983; 309: 280–83. Webster J, Piscitelli G, Poli A, Ferrari CI, Ismail I, Scanlon MF. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinaemic amenorrhea. N Engl J Med 1994; 331: 904–09.
Physiology Baird DT. The ovarian cycle. In: Hillier SG, ed. Ovarian endocrinology. Oxford: Blackwell Science, 1991: 1–24. Clarke IJ. GnRH and ovarian hormone feedback. Oxf Rev Reprod Biol 1987; 9: 54–95. Corner GW. Our knowledge of the menstrual cycle, 1910–1950. Lancet 1951; i: 919. Crowley WF Jr, Filicori M, Spratt DI, Santoro NF. The physiology of gonadotropin releasing hormone (GnRH) secretion in men and women. Recent Prog Horm Res 1985; 41: 473–525. Harris GW, Naftolin I. Hypothalamus and control of ovulation. Br Med Bull 1970; 26: 3–9. Hotchkiss J, Knobil E. The hypothalamic pulse generator: the reproductive core. In: Adashi EY, Rock JA, Rosenwalks Z, eds. Reproductive endocrinology, surgery and technology. Philadelphia: Lippincott Raven, 1995: 123–62.
Anatomical causes March CM. Acquired intrauterine adhesions: Asherman’s syndrome. In: Adasi EY, Rock JA, Rozenwalks Z, eds. Reproductive endocrinology, surgery and technology, vol 2. Philadelphia: Lippincott-Raven, 1995: 1475–88.
Hypergonadotropic hypogonadism Bardin CW, Bullock LP, Sherins RJ, et al. Androgen metabolism and mechanisms of action in male pseudohermaphroditism: a study of testicular feminization. Recent Prog Horm Res 1973; 29: 65–109. French FS, Lubahn DB, Brown TR, et al. Molecular basis of androgen insensitivity. Recent Prog Horm Res 1990; 46: 1–42. Jones SG, de Moraes-Ruehsen M. A new syndrome of amenorrhoea in association with hypergonadotropism and apparently normal ovarian follicular apparatus. Am J Obstet Gynecol 1969; 104: 597–600. Lutjen P, Trouson A, Leeton J, Findlay J, Wood C, Revoir P. The establishment and maintenance of pregnancy using in vitro fertilization and embryo donation in a patient with primary ovarian failure. Nature 1984; 307: 174–75. Muller J, Schwartz M, Skakkebaek NE. Analysis of the sex-determining region of the Y chromosome (SRY) in sex reversed patients: point mutation in SRY causing sex reversion in a 46XY female. J Clin Endocrinol Metab 1992; 75: 331–33. Rabinowe SL, George KL, Ravnikar VA, Dluhy RG, Dib SA. Premature menopause: monoclonal antibody defined T lymphocyte abnormalities and antiovarian antibodies. Fertil Steril 1989; 51: 450–59. Saenger P. Turner’s syndrome. N Engl J Med 1996; 335: 1749–54. Sohval AR. The syndrome of pure gonadal dysgenesis. Am J Med 1965; 38: 615–25. Starup J, Sele V, Henricksen B. Amenorrhoea associated with increased production of gonadotropins and a morphologically normal ovarian follicular apparatus. Acta Endocrinol (Copenh) 1971; 66: 248–56.
Hyperprolactinaemia Bohnet HG, Dahlen HG, Wuttke W, Schneider HPG. Hyperprolactinemic anovulatory syndrome. J Clin Endocrinol Metab 1976; 42: 132–43. Crosignani PG, Ferrari C. Dopaminergic treatments for hyperprolactinaemia. Baillière’s Clin Obstet Gynaecol 1990; 4: 441–55. Forbes AP, Hennemann PH, Griswold GC, Albright F. Syndrome characterized by galactorrhea, amenorrhea and low urinary FSH: comparison with acromegaly and normal lactation. J Clin Endocrinol Metab 1954; 14: 265–71. Gemzell C, Wang CF. Outcome of pregnancy in women with pituitary adenoma. Fertil Steril 1979; 31: 363–72. Gindoff PF, Loucopoulas A, Jewelewicz R. Treatment of hyperprolactinemic amenorrhea with pulsatile gonadotropin-releasing hormone therapy. Fertil Steril 1986; 46: 1156–61.
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Hypogonadotropic hypogonadism Berga SL, Mortola JF, Girton L, Suh B, Lauchlin GA, Pham P, Yen SSC. Neuroendocrine observations in women with functional hypothalamic amenorrhoea. J Clin Endocrinol Metab 1989; 68: 301–08. Lachelin GCL, Yen SSC. Hypothalamic chronic anovulation. Am J Obstet Gynecol 1978; 130: 825–31. Letterie GS, Coddington CC, Collins RL, Merriam GR. Ovulation induction using s.c. pulsatile gonadotrophin-releasing hormone: effectiveness at different pulse frequencies. Hum Reprod 1996; 11: 19–22. Sheehan HL. Simmond’s disease due to postpartum necrosis of the anterior pituitary. Q J Med 1939; 8: 277–309. Wildt L, Leyendecker G. Induction of ovulation by the chronic administration of naltrexone in hypothalamic amenorrhoea. J Clin Endocrinol Metab 1987; 64: 1334–35.
Normogonadotropic anovulation Adashi EY. Clomiphene citrate-induced ovulation. Semin Reprod Endocrinol 1986; 4: 255–76. Carey AH, Chan KL, Short F, White DM, Williamson R, Franks S. Evidence for a single gene effect in polycystic ovaries and male pattern baldness. Clin Endocrinol 1993; 38: 653–58. Carey AH, Waterworth D, Patel K, et al. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP 17. Hum Mol Genet 1994; 3: 1873–76. Fauser BCJM. Step-down follicle-stimulating hormone regimens in polycystic ovary syndrome. In: Filicori M, Flamigni C, eds. Ovulation induction: basic science and clinical advances. Amsterdam: Excerpta Medica, 1994: 145–52. Franks S. Polycystic ovary syndrome: a changing perspective. Clin Endocrinol 1989; 31: 87–120. Gharani N, Waterworth DM, Batty S, et al. Association of the steroid metabolising gene CYP 11␣ with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet 1997; 6: 397–402. Glasier AF. Clomiphene citrate. Baillière’s Clin Obstet Gynaecol 1990; 4: 491–501. Hague WM, Adams J, Reeders ST, Peto TE, Jacobs HS. Familial polycystic ovaries: a genetic disease? Clin Endocrinol 1988; 29: 593–605. Kazer RR, Kessel B, Yen SSC. Circulating luteinizing hormone pulse frequency in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1987; 65: 233–36. Kiddy DS, Sharp PS, White DM, et al. Difference in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: an analysis of 263 consecutive cases. Clin Endocrinol 1990; 32: 213–20. Polson DW, Kiddy D, Mason HD, Franks S. Induction of ovulation with clomiphene citrate in women with polycystic ovary syndrome: the difference between responders and non-responders. Fertil Steril 1989; 51: 30–34. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935; 29: 181–91. White DM, Polson DW, Kiddy D, et al. Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab 1996; 81: 3821–24.
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