Potential effects of progesterone, metformin, and spironolactone on hereditary angioedema

I have a 27 y/o female with HAE Type I who had been on Danazol 50mg daily for approximately 10 years (started by her previous physician). There was a question of whether or not she also had PCO (polycystic ovarian syndrome) although except for a minimal degree of facial acne and an irregular menstrual cycle she does not fit the clinical picture. Upon starting Cinryze, 1000 Units IVP every 4 days she was weaned off Danazol completely approximately 5 months ago. Her endocrinologist has advised her to start one of three meds for her presumed PCO including Spirinolactone, Metformin and Progesterone only oral birth control pills. Her question to me, thus my question to you, is the likelihood of developing any breakthrough attacks of HAE attributed to any of the above noted meds. A literature search was not very informative. Thank you very much.

Thank you for your inquiry.

I am not aware of metformin or spironolactone having any potential effect on a course of hereditary angioedema. Also I could not find, on a literature search, any evidence indicating that they exert an effect on the course of this condition.

However, the literature is replete with references to the effects of hormones on the course of hereditary angioedema. There are reports of progesterone both exacerbating and improving the course of this condition. I have copied below, for your convenience, abstracts of references and a reference of a review of the effects of hormones on hereditary angioedema. I have also copied below a quote from a recent reference from the Journal of Allergy and Clinical Immunology (Volume 129, Issue 2 , Pages 308-320, February 2012) , which I recommend for your review. This reference is a consensus guidelines regarding the gynecologic and obstetric management of female patients with hereditary angioedema.

Thank you again for your inquiry and we hope this response is helpful to you.

Hormonally Exacerbated Heredity Angioedema

Australasian Journal of Dermatology

Volume 33, Issue 1, pages 35¨C38, April 1992


Hereditary angioedema is a rare disorder which is associated with an inherited deficiency of the inhibitor of the activated first component of complement. Genetic transmission occurs in an autosomal dominant manner. Affected patients are heterozygotes, and their deficiency is incomplete, many of them having up to 20% of the normal amount of the inhibitor.1

We describe two cases of C1 esterase inhibitor deficiency occurring in a mother and daughter in whom the symptoms appeared to be related to the menstrual cycle or the taking of the oral contraceptive pill. Although both features have been mentioned in the literature, to the best of our knowledge premenstrual exacerbations have not been documented previously. We examined the likely basis of hormonally exacerbated hereditary angioedema.

Hereditary Angioedema Precipitated by Estrogen Replacement Therapy in a Menopausal Woman

American Journal of the Medical Sciences:

September 2000 - Volume 320 - Issue 3 - pp 212-213


We report the first documented case in the literature of hereditary angioedema presenting after commencement of estrogen replacement therapy for menopausal symptoms. The late presentation of the disease and the precipitation of attacks by physiological doses of estrogen replacement therapy make this a highly unusual case. The pathophysiology of hereditary angioedema and its hormonal links are discussed.

Sex hormones in hereditary angioneurotic oedema

Clinical Endocrinology

Volume 60, Issue 4, pages 508¨C515, April 2004


Objective: The fluctuations in sex hormone levels at the beginning of adolescence, in the perimenopausal period, during pregnancy or during the use of oral contraceptives can precipitate oedematous attacks in hereditary angioneurotic oedema (HANO). Attacks usually disappear after the onset of menopause. This study was undertaken to establish any relationship between the serum levels of sex hormones and the incidence of HANO attacks.

Patients and Measurements: Serum levels of LH, FSH, progesterone, oestradiol, testosterone, PRL and SHBG were measured in 78 patients [mean age 30¡¤3 years (range 4¨C70 years)] with HANO. A questionnaire was used to explore the medical history of adult patients to characterize the evolution and the characteristics of attacks.

Results: The number of attacks was significantly higher [odds ratio (OR) 6¡¤36 (1¡¤31¨C30¡¤81); P = 0¡¤022] in females with high progesterone levels (¡Ý 4 nmol/l), irrespective of age, menstrual cycle and danazol dose. The OR was even higher [13¡¤4 (2¡¤2¨C81¡¤4); P = 0¡¤005] when only subcutaneous attacks were considered. Multiple logistic regression analysis demonstrated a significantly lower attack frequency during 1-year follow-up in patients with a higher (40 nmol/l) SHBG level (OR 0¡¤25 (0¡¤07¨C0¡¤90); P = 0¡¤034). This difference existed independently of age and danazol dose.

Conclusion: In view of these results, the monitoring of progesterone and SHBG levels can prove useful in the prediction of attacks in hereditary angioneurotic oedema.

Effect of sex hormones on the complement-related clinical disorder of hereditary angioedema.

Frank MM.

Arthritis Rheum. 1979 Nov;22(11):1295-9.

International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency

The Journal of Allergy and Clinical Immunology

Volume 129, Issue 2, Pages 308-320, February 2012 Background

There are a limited number of publications on the management of gynecologic/obstetric events in female patients with hereditary angioedema caused by C1 inhibitor deficiency (HAE-C1-INH).

Objective: We sought to elaborate guidelines for optimizing the management of gynecologic/obstetric events in female patients with HAE-C1-INH.

Methods: A roundtable discussion took place at the 6th C1 Inhibitor Deficiency Workshop (May 2009, Budapest, Hungary). A review of related literature in English was performed.


Contraception: Estrogens should be avoided. Barrier methods, intrauterine devices, and progestins can be used. Pregnancy: Attenuated androgens are contraindicated and should be discontinued before attempting conception. Plasma-derived human C1 inhibitor concentrate (pdhC1INH) is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis. Tranexamic acid or virally inactivated fresh frozen plasma can be used for long-term prophylaxis if human plasma-derived C1-INH is not available. No safety data are available on icatibant, ecallantide, or recombinant human C1-INH (rhC1INH). Parturition: Complications during vaginal delivery are rare. Prophylaxis before labor and delivery might not be clinically indicated, but pdhC1INH therapeutic doses (20 U/kg) should be available. Nevertheless, each case should be treated based on HAE-C1-INH symptoms during pregnancy and previous labors. pdhC1INH prophylaxis is advised before forceps or vacuum extraction or cesarean section. Regional anesthesia is preferred to endotracheal intubation. Breast cancer: Attenuated androgens should be avoided. Antiestrogens can worsen angioedema symptoms. In these cases anastrozole might be an alternative. Other issues addressed include special features of HAE-C1-INH treatment in female patients, genetic counseling, infertility, abortion, lactation, menopause treatment, and endometrial cancer.

Quote from the Journal of Allergy and Clinical Immunology:

"Progesterone and progestins can alleviate hot flushes and can be offered to women who have HAE-C1-INH.167,168 Tibolone, a normethyltestosterone derivative used in symptomatic postmenopausal women, can also be used but should be given in place of rather than in combination with danazol because of a risk of greater side-effects because of their common properties.153"

Potential effects of progesterone, metformin, and spironolactone on hereditary angioedema