Fertility in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Fertility in women with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency appears to be reduced. The purpose of this review is to summarize the reported evidence about subfertility in women with CAH and to review the causes of reduced fertility. Compared with a non-CAH female population, pregnancy and live-birth rates are severely reduced in salt-wasting patients, mildly reduced in simple virilizing patients, and normal in nonclassical patients. Several factors have been suggested to contribute to the impaired fertility in CAH females: adrenal overproduction of androgens and progestins (17-hydroxyprogesterone and progesterone), ovarian hyperandrogenism, polycystic ovary syndrome, ovarian adrenal rest tumors, neuroendocrine factors, genital surgery, and psychological factors such as delayed psychosexual development, reduced sexual activity and low maternal feelings. It is obvious that these factors are interrelated. Improving endocrine, surgical, and psychological management could contribute to improving fertility chances in these patients. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader will be able to define the various types of CAH, to describe the fertility issues in the CAH patients, to outline the various other causes of hyperandrogenism, and to list the treatment options for the patient with CAH.     

Das adrenogenitale Syndrom

Congenital adrenal hyperplasia (CAH) is one of the most common inherited metabolic diseases following an autosomal recessive trait. There are five different enzyme defects leading to CAH. Steroid 21-hydroxylase deficiency is the most common form of CAH accounting for more than 90%. Phenotypically, CAH due to 21-hydroxylase deficiency can be subclassified into the non-classic and classic form. The classic form can be divided into the simple virilising and the salt-wasting form. The non-classic form is characterised by an excess of adrenal androgens, but no permanent glucocorticoid or mineralocorticoid deficiency. All patients with the classic form suffer from glucocorticoid deficiency and the subgroup of patients with the salt-wasting form additionally from mineralocorticoid deficiency. Therapy of the non-classic form aims to treat the symptoms of hyperandrogenism. In the classic form therapy consists of the substitution of the missing hormones, the glucocorticoids, and in the salt-wasting form also mineralocorticoids.     

Pregnancies in patients with congenital adrenal hyperplasia with complete or almost complete impairment of 21-hydroxylase activity

OBJECTIVE: To show that, with appropriate therapy, women with classic congenital adrenal hyperplasia (CAH) can become pregnant. DESIGN: Observational clinical study. SETTING: University hospital. PATIENT(S): Adult young women with CAH: three with the salt-wasting form and four patients with simple virilizing CAH due to severe homozygous or compound heterozygous mutations of the CYP21B gene (deletions, I172N in exon 4 and nt656A/C-->G in intron 2) who wished to become pregnant. INTERVENTION(S): After confirmation in the first patient of the beneficial effect of additional treatment with fludrocortisone in lowering 17alpha-hydroxyprogesterone (17-OHP) levels, five other patients were treated with hydrocortisone as three daily doses at 8-hour intervals and fludrocortisone 0.1-0.2 mg daily divided into two to three doses. One patient received glucocorticoid alone. MAIN OUTCOME MEASURE(S): Treatment was controlled on the basis of morning salivary 17-OHP estimates and plasma renin concentrations. RESULT(S): Nine pregnancies occurred in six women. The course of the pregnancies (except one spontaneous abortion) was normal without any other modification of therapy. Only the women treated with hydrocortisone alone did not become pregnant. CONCLUSION(S): When treated with a combination of glucocorticoids and mineralocorticoids, sexually active patients with the classic phenotype of CAH can become pregnant.     

Sonography in prenatal diagnosis of congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder with an incidence of 1/15 000. More than 90% of CAH cases result from mutations of CYP21, leading to 21-hydroxylase deficiency. In its classical form, CAH is severe and consists of the virilizing (increase of androgens) and salt-wasting (lack of aldosterone) phenotype. When a proband exists, early prenatal diagnosis for CAH can be performed by direct molecular analysis in the first trimester. We describe herein two cases suggesting that the prenatal diagnosis of CAH can be initiated by the sonographic appearance of the adrenal gland at the second-trimester scan in the absence of a family history.     

Influence of Genotype and Hyperandrogenism on Sexual Function in Women With Congenital Adrenal Hyperplasia

BackgroundDepending on CYP21A2 genotype, congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to biochemical alterations (including hyperandrogenism, hypocortisolism, and hypoaldosteronism) and a wide spectrum of phenotypic disease manifestation. The latter include life-threatening salt-wasting crises, prenatal virilization of genitalia in women (classic CAH [C-CAH]) as well as milder forms of the disease exclusively presenting with hirsutism, acne or reduced fertility (nonclassic CAH [NC-CAH]), and could influence sexual function and identity.AimThe present study evaluated sexual function, gender identification, and partner preference in women with C-CAH and NC-CAH.MethodsIn a cross-sectional cohort analysis, 35 female patients with CAH were divided into 2 groups: C-CAH (salt-wasting/simple virilizing; n = 17) and NC-CAH (n = 18) according to genotype and phenotype. Sexual function and sexual distress were assessed using established questionnaires, including the Female Sexual Function Index. Phenotype (defined by signs of hyperandrogenism) was assessed clinically (Ferriman-Gallwey score) and with the ovulatory function index. CYP21A2 genotype was determined by Sanger sequencing and multiplex ligation-dependent probe amplification. Sexual function was also separately analyzed in the context of clinical signs of androgenization in women with (n = 13) and without acne (n = 22).OutcomesThe study outcomes were sexual function and sexual distress in relation to genotype, clinical signs of androgenization, and biochemical parameters.ResultsWomen with NC-CAH had significantly lower orgasm scores, a trend toward lower sexual function with higher sexual distress, as well as biochemical evidence of hyperandrogenism (higher dehydroepiandrosterone sulfate and lower SHBG) and a trend toward more clinical signs of hyperandrogenism (hirsutism). Indicators of in utero and childhood androgen excess as well as the presence of acne in all patients were related to lower sexual function and higher sexual distress. Clinical signs of hyperandrogenism correlated well with cardiovascular and metabolic risk factors.Clinical TranslationWomen with NC-CAH and women with clinical signs of hyperandrogenism demonstrated higher distress compared to women with C-CAH and women without clinical signs of hyperandrogenism, respectively, regarding different aspects of sexual function.ConclusionsThese data underline the importance of early diagnosis and therapy initiation, especially in patients with NC-CAH.Schernthaner-Reiter MH, Baumgartner-Parzer S, Egarter HC, et al. Influence of Genotype and Hyperandrogenism on Sexual Function in Women With Congenital Adrenal Hyperplasia. J Sex Med 2019;16:1529–1540.     

Neonatal screening for congenital adrenal hyperplasia in Taiwan: a pilot study.

BACKGROUND AND PURPOSE: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder with defects in steroidogenesis. Its wide and non-specific clinical spectrum poses problems for early diagnosis. Without a screening program, affected newborns may be missed, even though they have a life-threatening illness. The purpose of this study was to survey the prevalence and phenotype of CAH in Taiwan by neonatal screening. METHODS: From March 1, 2000, to August 31, 2001, 192,687 capillary blood spots were collected nationwide. Enzyme-linked immunosorbent assay (ELISA) was used to quantitatively measure 17-hydroxyprogesterone (17-OHP) in all specimens. RESULTS: Thirteen cases of CAH (7 female and 6 male) were detected, resulting in an estimated prevalence of 1:14,822. Nine patients (69%) had salt-wasting CAH and four (31%) had simple virilizing CAH. All cases were identified before clinical diagnosis, and also before the development of adrenal crisis. CONCLUSION: This study estimated that 20 babies with CAH are born each year in Taiwan. A nationwide neonatal screening program is the only way to provide early diagnosis and prompt treatment. This would save lives and enhance the health of affected infants.     

Introduction

Although the wish for a child may be ambivalent in women with anorexia or bulimia nervosa, the prevalence of eating disorders in fertility clinics is probably underestimated. Motivated by the wish for a child, these couples may be reluctant to reveal a history of an eating disorder and/or show resistance to some therapy for this disorder. Nevertheless, in our opinion, the eating disorder must be in full remission before any fertility treatment can start, if treatment is still necessary at that moment. Illustrated with some case examples, we will discuss the major problems and clinical strategies in the management of these complex cases, based upon the experience in our own fertility clinic.     

Are there indications for cryogenically preserving ovarian tissue in gynecologic oncology?

One of the essential goals of ovarian tissue cryopreservation is to preserve the fertility of young women who will be undergoing sterilizing anticancer treatments, as cryopreservation of sperm serves in men. However, maturation of gametes after thawing has not yet been realized in humans and pregnancies have only been obtained in animal models. It is nonetheless possible today to cryopreserve the ovarian tissue of patients who have nothing to lose as their follicular reserve would in any case be destroyed or severely depleted by cancer treatment. In gynecologic oncology, ovarian tissue cryopreservation may be performed when curative or prophylactic ovariectomy must be undergone, or when chemotherapy with high-dose alkylating agents is planned, particularly in cases requiring chemotherapy combined with pelvic radiation. These clinical situations may be encountered in young women and especially in girls with early-onset forms of ovarian, cervical, uterine, or vaginal cancers. These situations, nevertheless, remain rare as gynecological cancers occur most often in the post-menopausal woman.     

The management of eating disorders in a fertility clinic: clinical guidelines.

Although the wish for a child may be ambivalent in women with anorexia or bulimia nervosa, the prevalence of eating disorders in fertility clinics is probably underestimated. Motivated by the wish for a child, these couples may be reluctant to reveal a history of an eating disorder and/or show resistance to some therapy for this disorder. Nevertheless, in our opinion, the eating disorder must be in full remission before any fertility treatment can start, if treatment is still necessary at that moment. Illustrated with some case examples, we will discuss the major problems and clinical strategies in the management of these complex cases, based upon the experience in our own fertility clinic.     

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) due to P450c21 (21-hydroxylase deficiency) is a common autosomal recessive disorder. This disorder is due to mutations in the CYP21A2 gene which is located at chromosome 6p21. The clinical features reflect the magnitude of the loss of function mutations. Individuals with complete loss of function mutations usually present in the neonatal period. The clinical features of individuals with mild loss of function mutations are predominantly due to androgen excess rather than adrenal insufficiency leading to an ascertainment bias favoring diagnosis in females. Treatment goals include normal linear growth velocity and "on-time" puberty in affected children. For adolescent and adult women, treatment goals include regularization of menses, prevention of progression of hirsutism, and fertility. This article will review key aspects regarding pathophysiology, diagnosis, and treatment of CAH.     

体外受精治疗非典型21-羟化酶缺乏症患者成功妊娠1例

目的 21-羟化酶缺乏症(21-OHD)、17α-羟化酶缺乏症(17-OHD)为先天性肾上腺皮质增生的2种类型,因酶缺乏程度不同,临床表现不一又分为多种亚型,其中非典型21-OHD与不完全型17-OHD皆症状轻微,临床不易发现,目前此类患者妊娠率较正常者低下,如何鉴别疾病,改善临床预后并提高生育能力是临床诊治及随访的重点。方法对本院生殖中心1例罕见的非典型21-OHD合并人细胞色素P450c17A1(CYP17A1)、卵泡刺激素受体(FSHR)、黄体生成素受体(LHCGR)基因多态性病例的诊断、治疗及促排卵的过程进行回顾性分析。结果该患者经基因型检测获得明确诊断,高孕酮血症及时得到治疗,并予以个体化促排卵方案,最终获得良好妊娠结局。结论生殖科临床医生应提高对先天性肾上腺皮质增生的认识,适当利用基因型分析协助诊断,在助孕过程中灵活制定个体化促排卵方案。     

Radiation damage to the uterus — Review of the effects of treatment of childhood cancer

At the present time approximately 1 in 1000 young people aged between 16 and 35 years will have been cured of cancer in childhood and some of the treatment regimens used will have predictable effects on their future fertility prospects. In young women who have been exposed to radiotherapy below the diaphragm, the reproductive problems include the risk of ovarian failure and significantly impaired development of the uterus. The magnitude of the risk is related to the radiation field, total dose and fractionation schedule. Premature labour and low birth weight infants have been reported after flank abdominal radiotherapy. Female long-term survivors treated with total body irradiation and marrow transplantation are also at risk of ovarian follicular depletion and impaired uterine growth and blood flow, and of early pregnancy loss and premature labour if pregnancy is achieved. Despite standard oestrogen replacement, the uterus of these young girls is often reduced to 40% of normal adult size. Uterine volume correlates with the age at which radiation was received. Regrettably, it is likely that radiation damage to the uterine musculature and vasculature adversely affects prospects for pregnancy in these women. It has been demonstrated that, in women treated with total body irradiation, sex steroid replacement in physiological doses significantly increases uterine volume and endometrial thickness, as well as re-establishing uterine blood flow. However, it is not known whether standard regimens of oestrogen replacement therapy are sufficient to facilitate uterine growth in adolescent women treated with total body irradiation in childhood. Even if the uterus is able to respond to exogenous sex steroid stimulation, and appropriate assisted reproductive technologies are available, a successful pregnancy outcome is by no means ensured. The uterine factor remains a concern and women who are survivors of childhood cancer and their carers must recognize that these pregnancies will be at high risk.     

Woman with virilizing congenital adrenal hyperplasia and leydig cell tumor of the ovary

We report the case of a 36-year-old woman with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, and corticosteroid replacement therapy since birth. She manifested persistent virilization and high testosterone levels that were attributed to nonadherence to medical treatment. The patient was referred to our gender unit for genitoplastic surgery. We recommended the patient for left oophorectomy after detecting an ovarian mass. Pathologic findings confirmed an ovarian hilus cell tumor. Testosterone levels fell back to normal and masculinization disappeared but ACTH remained elevated. This case represents a very rare type of primary ovarian tumor that must be considered in persistent virilizing symptoms in women with CAH.     

Radiation damage to the uterus -- review of the effects of treatment of childhood cancer

At the present time approximately 1 in 1000 young people aged between 16 and 35 years will have been cured of cancer in childhood and some of the treatment regimens used will have predictable effects on their future fertility prospects. In young women who have been exposed to radiotherapy below the diaphragm, the reproductive problems include the risk of ovarian failure and significantly impaired development of the uterus. The magnitude of the risk is related to the radiation field, total dose and fractionation schedule. Premature labour and low birth weight infants have been reported after flank abdominal radiotherapy. Female long-term survivors treated with total body irradiation and marrow transplantation are also at risk of ovarian follicular depletion and impaired uterine growth and blood flow, and of early pregnancy loss and premature labour if pregnancy is achieved. Despite standard oestrogen replacement, the uterus of these young girls is often reduced to 40% of normal adult size. Uterine volume correlates with the age at which radiation was received. Regrettably, it is likely that radiation damage to the uterine musculature and vasculature adversely affects prospects for pregnancy in these women. It has been demonstrated that, in women treated with total body irradiation, sex steroid replacement in physiological doses significantly increases uterine volume and endometrial thickness, as well as re-establishing uterine blood flow. However, it is not known whether standard regimens of oestrogen replacement therapy are sufficient to facilitate uterine growth in adolescent women treated with total body irradiation in childhood. Even if the uterus is able to respond to exogenous sex steroid stimulation, and appropriate assisted reproductive technologies are available, a successful pregnancy outcome is by no means ensured. The uterine factor remains a concern and women who are survivors of childhood cancer and their carers must recognize that these pregnancies will be at high risk.     

Nichtklassisches adrenogenitales Syndrom

Adrenogenital syndrome (AGS) is an etiologically and clinically heterogeneous pattern of symptoms, which have a disorder in the biosynthesis of cortisol in common. The most commonly occurring disorder is a defect in 21-hydroxylase. If this is present as a homozygote, a differentiation is made between classical and nonclassical AGS. Nonclassical AGS mostly becomes apparent in the peripubertal or postpubertal phase due to symptoms of hyperandrogenemia, which can impair fertility. By impletation of an adrenocorticotropic hormone (ACTH) test homocygote and heterocygote carriers can be identified as well as unaffected women. Furthermore, heterozygote carriers and unaffected patients can also be identified. If the ACTH test indicates a nonclassical AGS, molecular diagnostics including consultation and clarification should be performed. The treatment of nonclassical AGS is dependent on the clinical symptoms and the residual activity of the enzyme. In adult women treatment is carried out with hydrocortisone or synthetic glucocorticoids. In women with no desire to have children, the combination of an oral contraceptive with antiandrogenic gestagens is recommended for symptom relief. In order to maintain fertility a form of sterility treatment is carried out corresponding to the treatment of patients with hyperandrogenemia.     

Fertility-Sparing Management Using Progestin for Young Women with Endometrial Cancer From a Population-Based Study

Objective

For young women with complex atypical endometrial hyperplasia (CAH) and endometrial cancer (EC) who choose to preserve fertility, progestin therapy is the mainstay of treatment. The objective of this study was to evaluate oncologic and reproductive outcomes associated with progestin therapy among these women from a population-based cancer registry.

Update on the medical treatment of endometriosis

The treatment of women with endometriosis can be a challenge. Therapeutic strategies must be tailored to the individual symptoms, age, and desire for fertility. Medical therapy continues to be based on endocrine treatment, such as oral contraceptives, progestins, danazol, and GnRH agonists. Unfortunately, recurrence rates are high after discontinuation of therapy. Recent clinical research on GnRH analogues plus add-back therapy has produced favorable results. Long-term treatment of patients using this approach has successfully reduced pain while minimizing symptoms of hypoestrogenism and adverse metabolic effects, such as loss of bone mineral density. Currently, GnRH analogues given with add-back therapy seems to be the most effective long-term approach to the treatment of symptomatic endometriosis. In the future, other modalities, such as medicated vaginal rings, inhibitors of steroidogenic enzymes, and GnRH antagonists, will most likely be options.     

Schilddr��sendiagnostik und -therapie in der t?glichen Praxis

Thyroid dysfunction and structural changes of the thyroid are common diseases which affect women more often than men. A distinction is made between latent and overt thyroid dysfunction. In cases of overt dysfunction the concentrations of free thyroid hormones are altered. Both hypothyroidism and hyperthyroidism can be caused by a variety of mechanisms. A manifest failure is always an indication for therapy. In cases of fertility desire or pregnancy a latent hypothyroidism also needs therapy by thyroid hormone substitution. In Germany one third of the population have structural changes such as an enlarged thyroid or adenomatous goitre. Medicinal treatment, radioiodine therapy and thyroid surgery are available for treatment.     

Fertility sparing treatment of complex atypical hyperplasia and low grade endometrial cancer using oral progestin

Objective

Oral progestin is an alternative to hysterectomy for women with complex atypical hyperplasia (CAH) or grade one endometrial cancer (G1EC) who wish fertility preservation. We evaluated treatment efficacy and fertility outcomes in this population.

Methods

Women < 45 y treated with oral progestin for CAH or G1EC were identified from two cancer centers. Data were obtained from medical records and telephone questionnaires. Time until complete response (CR), and from CR until recurrence was censored for patients without events and analyzed for associations with patient and treatment characteristics; cumulative incidence functions were used to estimate event probability over time.

Results

44 patients were identified, 19 (43%) with CAH and 25 (57%) with G1EC. Median age was 36.5 y (26–44). 24 (55%) achieved CR (median time: 5.7 months). Older age was associated with a lower likelihood of CR (HR 0.84, p = 0.0003, 95% CI, 0.8–0.9). CR probability appeared to plateau after 12 months of therapy. Among those with CR, 13 (54%) recurred (median time 3.5 y). 24 patients (55%) underwent hysterectomy; 3 (13%) were upstaged. 11 (25%) underwent fertility treatment with the following outcomes: 6 (55%) no pregnancy, 2 (18%) at least one live infant, and 3 (27%) spontaneous abortion. One achieved a live birth without intervention.

Conclusion

Oral progestin is an effective temporizing fertility-sparing treatment for women with CAH/G1EC. Fertility specialist involvement is recommended due to the low live birth rate without intervention. Progestin therapy should be re-evaluated at 1 year in non-responders due to a low probability of success. Hysterectomy is recommended after childbearing due to a high recurrence rate.     

Management of endometrial cancer in young women

Endometrial cancer is the most common gynecologic cancer and its incidence is rising among premenopausal women. Hysterectomy and bilateral salpingo-oophorectomy, traditional treatment for endometrial cancer, causes loss of fertility and ovarian function, both of which can significantly negatively impact a young woman's physical and mental well-being. Recently, conservative management with progestational agents has been reported with success from both oncologic and reproductive perspectives. However, there are no randomized trials comparing conservative versus surgical therapy. Patients who are candidates for conservative therapy must be extensively counseled regarding the risks and must comply with close surveillance.