International Journal of Gynecology & Obstetrics 71 Ž2000. 141᎐145
Hypogonadotropic hypogonadism: retrospective analysis of 19 cases M.D. MouraU , P.A.A.S. Navarro, M.F. Silva de Sa, ´ R.A. Ferriani, S.M. Unzer, R.M. Reis Department of Gynecology and Obstetrics, Uni¨ ersity of Sao ˜ Paulo, Ribeirao ˜ Preto, Brazil Received 5 November 1999; received in revised form 29 March 2000; accepted 5 April 2000
Abstract Objecti¨ es: To survey the clinical data of patients with isolated gonadotropin deficiency. Methods: We retrospectively surveyed the medical records of 19 patients with isolated gonadotropin deficiency aged 16᎐31 years Žmean: 20 years.. The major complaint was primary amenorrhea in 100% of the patients, with 42.1% of them also reporting absence of secondary sex traits, and 10% reporting anosmia or hyposmia. Seventy-four percent of the patients had been submitted to hormonal replacement therapy. Results: Bone densitometry was determined in 5 patients and revealed lumbar spine osteopenia in 3 patients and femoral osteopenia in 1. An association with urologic malformations was detected in 10.5% of cases and an association with gynecologic malformations was detected in 31.6%. Conclusions: Isolated gonadotropin deficiency can be easily diagnosed but requires early estrogen replacement therapy because of a higher risk of osteopenia and consequently of osteoporosis. Concomitant urogenital malformations are frequent and should be investigated. 䊚 2000 International Federation of Gynecology and Obstetrics. All rights reserved. Keywords: Isolated gonadotropin deficiency; Amenorrhea; Gynecologic malformations; Hypogonadotropic hypogonadism; Rokitansky syndrome; Mullerian defects
Corresponding author. Department of Gynecology and Obstetrics, Faculty of Medicine of Ribeirao ˜ Preto, USP, 14049-900 Ribeirao ˜ Preto, SP, Brazil. Tel.: q55-016-633963; fax: q55-016-6330946. E-mail address: [email protected]
ŽM.D. Moura.. 0020-7292r00r$20.00 䊚 2000 International Federation of Gynecology and Obstetrics. All rights reserved. PII: S 0 0 2 0 - 7 2 9 2 Ž 0 0 . 0 0 2 6 7 - 8
M.D. Moura et al. r International Journal of Gynecology & Obstetrics 71 (2000) 141᎐145
1. Introduction The first description of the association between hypogonadotropic hypogonadism and the absence of the olfactory system was reported by Maestre de San Juan w18x in the 19th century. In 1944, Kallmann et al. w14x studied a group of male individuals with anosmia and eunochoidism. At present, female patients with hypogonadotropin hypogonadism are divided into two major groups: with anosmia andror hyposmia ŽKallmann syndrome, KS. and without olfactory disorders Židiopathic hypogonadotropic hypogonadism.. Inheritance seems to be multifactorial and many cases occur sporadically. Some studies have demonstrated an association between isolated gonadotropin deficiency ŽIGD. and autosomal dominant X-linked inheritance with variable expression or autosomal recessive inheritance. The estimated incidence of KS is 1:50 000 women and 1:10 000 men w6x. The pathological findings include absence of the olfactory bulbs and tracts and a wide variety of hypothalamic alterations w8,9x. In 1992 Crowley et al. w5x reviewed the central mechanisms of control of the reproduction and physiopathology of the disease. Glass et al. w10x studied gonadotropin release in a female patient with hypogonadotropin hypogonadism and anosmia. The induction of ovulation in women with hypogonadotropic hypogonadism was discussed by Aharoni et al. w2x who reported a case of twin pregnancy in one of these patients. A review by Jones and Kemmann w13x reported that ovulation was induced in only 8 of 14 patients treated with human menopausal gonadotropin ŽhMG. and chorionic gonadotropin ŽhCG. and that the women who ovulated required high hMG Table 1 Signs and symptoms of 19 patients with isolated gonadotropin deficiency Major complaint
Primary amenorrhea Absence of secondary sex traits Anosmia or hyposmia
19 8 2
100 42.1 10.1
Table 2 Family history of 19 patients with isolated gonadotropin deficiency Family history
Twin sister Sisters Aunts
1 1 1
5.3 5.3 5.3
doses. Several studies w12,17,20x have demonstrated an association of abnormalities of various systems Žcardiovascular, renal, skeletal, gastrointestinal and craniofacial systems. with IGD. In the present retrospective study we surveyed the clinical data of patients with a diagnosis of IGD.
2. Material and methods We studied retrospectively 19 female patients with a diagnosis of IGD seen at the University Hospital of Ribeirao ˜ Preto from January 1980 to July 1998. The diagnostic criteria were based on signs and symptoms of hypogonadism, low LH and FSH levels and imaging examinations Žskull X-ray, computer tomography andror nuclear magnetic resonance. showing no alterations of the hypothalamus or the pituitary. The following variables were analyzed: age, symptoms, family history, hormonal replacement treatment, bone densitometry, and associated malformations.
3. Results Mean patient age was 20 years Žrange: 16᎐31 years.. The major complaint was primary amenorrhea in 100% of the patients, with 42.1% of them also reporting absence of secondary sex traits and 10.5% reporting anosmia or hyposmia ŽTable 1.. Three patients Ž15.9%. reported a family history Žaunts or sisters . of primary amenorrhea ŽTable 2..
M.D. Moura et al. r International Journal of Gynecology & Obstetrics 71 (2000) 141᎐145 Table 3 Urogenital malformations in patients with isolated gonadotropin deficiency Malformation
Rokitansky syndrome Uterine agenesis Unicorn uterus Pelvic kidneys Right renal agenesis
3 2 1 1 1
15.8 10.5 5.3 5.3 5.3
None of the patients studied was submitted to induction of ovulation with gonadotropins. Seventy-four percent of the patients were submitted to hormonal replacement therapy ŽHRT.. The remaining ones were not submitted to HRT because they were in the final stage of investigation, because they refused treatment or because they were lost to follow-up. Bone densitometry was performed in only 5 patients and demonstrated lumbar spine osteopenia in 3 and femoral osteopenia in 1 Žthe latter also having lumbar spine osteopenia.. An association with urologic malformations was observed in 10.5% of cases and an association with gynecologic malformations was observed in 31.2% ŽTable 3.. The most frequent gynecologic malformation was Rokitansky syndrome which was present in three patients Ž15.8% of IGD cases.. It should be pointed out that one of the patients with Rokitansky syndrome also had bilateral pelvic kidneys.
4. Discussion Isolated gonadotropin deficiency is a rare affection of relatively easy diagnosis. For the present patients, mean age at diagnosis was 20 years, a time when all patients sought medical care due to primary amenorrhea. It has been demonstrated that the osteoporosis that sets in among young hypoestrogenic patients is due more to accelerated bone loss than to decreased bone formation w30x, as confirmed by
increased serum levels of osteocalcin Ža marker of bone turnover. w23x. Although bone densitometry was performed in only five patients, 60% of them presented osteopenia, with a consequent need for early estrogen replacement w21x. It is known that this syndrome is characterized by failure of embryonic migration of both olfactory and GnRH-producing neurons w4x. The latter normally originate in the medial olfactory plate, cross the nasal septum and establish axodendritic synapses in the prosencephalon. Without the formation of these synapses the neurons do not cluster in the hypothalamus and the olfactory bulbs and tracts are not formed or are formed in an anomalous manner, generating the hypogonadotrophic hypogonadism and anosmia characteristic of KS w24x. Three patients had a family history of primary amenorrhea with hypogonadotropic hypogonadism. Recent clinical, cytogenetic, molecular and pathological studies have shown a form of X-linked Kallmann syndrome. Cloning of the supposed ‘K’ gene on the distal portion of the short arm of chromosome X was reported in 1991, and missence and nonsense mutations and full or partial deletions have been identified since then. This supposed ‘K’ gene codes for a protein whose structure suggests that this is an adhesion molecule involved in embryonic neuronal migration, whose deficiency may cause deficient neuronal migration both in the olfactory and GnRHproducing neurons w7,15x. However, most studies in women demonstrated that hypogonadism with or without anosmia was related to an autosomal gene defect w1,5,11,19,25,27x either involving an autosomal dominant gene with incomplete expression or an autonomic recessive gene. The autosomal genes involved in the etiopathogenesis of KS have not been identified. We detected an association with gynecologic malformations in 31.6% of our patients and an association with urologic malformations in 10.5%. With an analogy to men, for whom incomplete differentiation of the Wolffian duct w29x has been reported, we detected the presence of a unicorn uterus in 1 patient and uterine agenesis in 4 Žtwo of the latter patients presented Rokitansky syndrome.. It is not clear whether these malforma-
M.D. Moura et al. r International Journal of Gynecology & Obstetrics 71 (2000) 141᎐145
tions are associated with IGD or if this was a coincidental finding. It has been postulated that defects of formation and fusion of Mullerian ducts ¨ may be secondary to the absence of fetal gonadal᎐pituitary᎐hypothalamic function w3x. However, if this were the case, all patients with IGD should have gynecologic alterations. Another possibility would be an increase in the levels of Muller inhibitory factor, which is not only associ¨ ated with Muller duct reduction in male embryos, ¨ but also leads to interruption of oocyte meiosis w28x. This may explain the low pregnancy rates and the high doses of hMG necessary for the induction of ovulation in these patients. With respect to the association of IGD with urologic abnormalities, some studies have reported the presence of unilateral renal agenesis w22,26x as well as urethral anomalies w16x. In the last study cited, Levy and Kunidtizon w16x reported a case of Kallmann syndrome affecting two sisters with urethral anomalies. As a conclusion, we emphasize the wide heterogeneity of clinical manifestations associated with IGD and the need for early hormonal replacement therapy, and investigation of family history and of concomitant anomalies of other organs and systems, with special consideration of urogenital alterations. References w1x Adashi EJ, Hennebold JD. Single-gene mutations resulting in reproductive dysfunctions in women. New Engl J Med 1999;340Ž9.:709᎐718. w2x Aharoni A, Tal J, Paltieli Y. Kallmann syndrome: a case of twin pregnancy and review of the literature. Obstet Gynecol Surv 1989;44:491᎐499. w3x Brandenberger AW, Haenggi W, von Fisher B. Kallmann syndrome and associated malformation of the uterus. Fertil Steril 1994;61Ž2.:395᎐397. w4x Bick D, Franco B, Sherins RJ. Brief report: intragenic deletion of the KALIG-1 gene in Kallmann syndrome. N Engl J Med 1992;326:1752᎐1755. w5x Crowley WF, Jameson L. Gonadotropin-releasing hormone deficiency: perspectives for clinical investigation. Endocrinol Rev 1992;13:635᎐640. w6x Dean JC, Johnston AW, Klopper AI. Isolated hypogonadotropic hypogonadism: a family with autosomal dominant inheritance. Clin Endocrinol 1990;32:341᎐347.
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