The hormonal profile we are told is in menopausal range (FSH >20; estradiol <5) and the patient has systemic vasomotor symptoms. Therefore, it would be more appropriate to administer systemic estrogens. To compensate, she already has a local uterine progestin (levonorgestrel IUD).

A 43-year-old woman with a levonorgestrel intrauterine device who consults for lack of rest at night with the appearance of heat and palpitations. In the analytical analysis highlights free T4 10.5 pmol/L (9-19), thyrotropin 2.1 mIU/L (0.30-5.00), FSH 95.6 IU/L (1.38-16.7), LH 21 IU/L (2.4-9.3), estradiol < 0.07 nmol/L (0.07 - 1.14). What is the most appropriate treatment?

Oral estrogens and progestogens in continuous regimen.

Transdermal estrogens in a continuous regimen.

A 60-month non-comparative study on bleeding profiles with the levonorgestrel intrauterine system from the late transition period to estrogen supplemented menopause.

The primary aim of this study was to assess the transition from using the levonorgestrel-releasing intrauterine system (LNG IUS, 20 μg LNG/24 h) for reproductive-age contraception to using it as menopausal-age endometrial protection during estrogen replacement therapy (ERT). The transfer process was evaluated by assessment of the vaginal bleeding pattern. Continuation rates were also recorded. Open, multicentre, non-comparative study was conducted in 11 menopausal centres in Finland (3), The Netherlands (4), Belgium (2) and UK (2). Three hundred and ninety-four healthy women aged 46-51 years at entry with regular menstrual cycles, but without any climacteric symptoms, and who were willing to start oral or transdermal estrogen treatment for climacteric symptoms. If by 48 months a woman was not menopausal, she was not eligible for the ERT phase. Bleeding patterns were recorded in 90-day reference periods. One hundred and sixty-eight women were eligible for the ERT phase. The mean ± SD number of bleeding/spotting days was highest (49 ± 19 days) in the first 90-day reference period in the contraceptive phase. For subjects who switched to ERT this number was 10 ± 13 days in the last contraceptive reference period and decreased to 9 ± 12 days in the first and 6 ± 10 days in the last 90-day reference period of the ERT phase. For both spotting and bleeding days there was no statistically significant difference between the last contraceptive and the first reference period of the ERT phase. In general, the results indicate that continuing with the LNG IUS from contraception to ERT has no adverse effects on the vaginal bleeding profile, and show a positive effect of the combined estrogen and LNG IUS treatment on the quality of life.

Continuous combined parenteral estrogen substitution and intrauterine progestogen delivery: the ideal HST combination?

To evaluate ease of insertion, acceptability and endometrial safety of a novel, miniature intrauterine, T-shaped, levonorgestrel (LNG)-releasing intrauterine system (IUS), Femilis Slim LNG-IUS (Contrel Research, Belgium), combined with parenteral estrogen substitution therapy (EST) in postmenopausal women. A prospective, non-comparative, study in postmenopausal women. A 3.0 cm long and 2.0 mm wide coaxial fibrous delivery system, delivering approximately 20 microg/day of levonorgestrel (LNG) was used. The drug compartment is provided with crossarms fixed to the upper part of the drug delivery rod. The calculated duration of release of the system is at least 5 years. The majority of women received percutaneous 17beta estradiol (Oestrogel, Besins Int., Belgium), 1.5 mg daily on a continuous basis, which provides sufficient blood levels of estrogen in most women to suppress climacteric symptoms and protection against bone loss. ease of insertion, retention and side effects of the T-LNG Slim IUS. endometrial safety assessed by transvaginal ultrasound examination and by endometrial biopsy in a subset of women. One hundred and seventy insertions were performed in postmenopausal women with median age of age 56.6 (range 43.5-80.3). Insertion was easy in 161 (94.2%) and difficult in 9 (5.3%) women. Pain at insertion was rated as none in 57 women (33.5%), mild in 105 (61.7%), moderate in 7 (4.1%) and severe in 1 (0.5%) woman. The system was well retained in the uterus as no expulsions occurred. At the time of study analysis, the total number of women-months was 1797.5. Ninety-five women had the T-LNG-IUS in place for periods in excess of 1 year. The study was well followed-up with lost-to-follow-up rate (defined as no follow-up during 12 months) of zero at the time of study analysis. The number of women continuing the method was 160 (94.1%) including four women which were released from follow-up for various non-medical related reasons. The histological examinations conducted in 105 women showed predominantly inactive endometrium characterized by a pseudo-decidual reaction of the endometrial stroma with endometrial atrophy. The mean thickness (double-layer) of the endometrium was 3.3 mm (range 2-5 mm) which correlated well with the histology results. The results suggest that the small T-LNG-IUS is easy to insert in most postmenopausal women without anaesthesia and dilatation of the cervix. It is well tolerated, well accepted and effective in suppressing the endometrium during EST. The lack of expulsions of the device in this study is attributed to the optimal design characteristics of the IUS, the absence of uterine bleeding and absent or reduced contractility of the uterus. The study confirms earlier studies conducted with other LNG-releasing systems used for endometrial suppression during EST. The ease of insertion of the small LNG-IUS could be an important incentive to expand the use of the continuous combined regimen with local delivery of the progestogen. It could be a method of choice for endometrial suppression in women using EST with fundamental advantages to systemically applied progestogens which have been the subject of considerable debate as reported in the recent literature.

Long-term treatment with transcutaneous estradiol and oral medroxyprogesterone acetate.

In an open prospective study with therapeutic monitoring, 34 women with climacteric symptoms, FSH > 40 IU/L and LH > 25 IU/L were treated for 12 months with an estradiol-depot-patch (Estraderm TTS) 50 micrograms twice a week and medroxyprogesterone acetate 10 mg tablets from 12th to 25th day of cycle. During the first months a significant improvement was seen in hot flushes and other climacteric inconveniences in terms of Kupperman's menopause index. During the study period FSH and LH were suppressed and the estrogen values were normalized. The fraction of free estradiol compared to protein bound estradiol remained unchanged during the whole treatment. The serum-lipids and serum-SHBG at inclusion were within normal limits and did not change during 12 months of treatment. Thus from these parameters no sign of any liver induction was seen. Ten patients had short term skin symptoms while four withdrew from the study because of persistent skin symptoms. Nine patients withdrew from the study, in five cases this was related to the therapy while in the other four it was due to other causes. Twenty-five (74%) women wished to continue the treatment after 12 months.

Gynecology_Novak

Table 34.1 Hormone Therapy Options Table 34.1 Continued 17β-estradiol (E) + levonorgestrel (P) Climara Pro 0.045 mg E + 0.0015 mg P once weekly E, estrogen; P, progestin. Products available in the United States. Table modified and used with permission; North American Menopause Society; www.menopause.org. also effectively treats hot ﬂashes for many women. Low-dose oral esterified and conjugated estrogens (CE) (0.3 mg daily), oral estradiol (0.5 mg daily), and transdermal estradiol (0.025 and 0.014 mg weekly) often are effective and associated with minimal side effects and endometrial stimulation (15–17). Progestin therapy must be given concurrently if a woman has not had a hysterectomy, although with low-dose estrogen therapy, intermittent progestin treatment may be an option.

Endometrial safety after 5 years of continuous combined transdermal estrogen and intrauterine levonorgestrel delivery for postmenopausal hormone substitution.

To investigate endometrial histology and thickness of the endometrium after long-term use of continuous transdermal estrogen substitution combined with intrauterine release of levonorgestrel (LNG) in postmenopausal women. A 5-year non-comparative prospective clinical trial. Out of 182 symptomatic postmenopausal women using estrogen substitution therapy (EST) combined with a novel T-shaped LNG-releasing intrauterine system (Femilis Slim LNG-IUS), to prevent endometrial proliferation and bleeding, only those women (n=102) who used two consecutive LNG-IUSs, were isolated with the aim to study the long-term effects on the endometrium. The mean age of the women was 57 years (range 47-71). The majority of women received percutaneous 17beta estradiol, 1.5mg daily, or an equivalent dose by patch or orally, on a continuous basis. Endometrial histology and ultrasonographic evidence of endometrial suppression, after a period of approximately 5 years of use. The mean duration of use of the regimen was 70 months (range 25-98). The dominant endometrial histologic picture was that of inactive endometrium characterized by glandular atrophy and stroma decidualization (Kurman classification 5b). No cases of endometrial hyperplasia were found. On transvaginal ultrasound, this corresponds with a thin endometrium (< or = 5 mm). The results of this 5-year study in 102 postmenopausal women using EST demonstrates that the LNG-IUS effectively opposes the estrogenic effect on the endometrium resulting in strong suppression during the entire period of EST. Due to its high efficacy and absence of systemic effects on organ tissues (e.g., breasts), target delivery in the uterine cavity could be a preferred route to administer a progestagen in women using EST.

List of estrogens available in the United States

Estradiol/progesterone (TX-001HR), a combination of estradiol and progesterone in oil-filled capsules, is currently pending approval. Transdermal patches Estradiol and levonorgestrel (Climara Pro) – 45 μg/24 hours / 15 μg/24 hours Estradiol and norethisterone acetate (Combipatch) – 50 μg/24 hours / 0.14 mg/24 hours; 50 μg/24 hours / 0.25 mg/24 hours Combined with other medications Oral pills Conjugated estrogens and bazedoxifene acetate (Duavee) – 20 mg / 0.45 mg See also List of sex-hormonal medications available in the United States List of estrogens List of estrogen esters Oral contraceptive formulations Estradiol-containing oral contraceptive Notes References External links For Women: Menopause—Medicines to Help You – U.S. Food and Drug Administration Estrogens Hormonal contraception

Gynecology_Novak

Systemic estrogen therapy is the most effective treatment for vasomotor symptoms and the only therapy currently approved by the U.S. Food and Drug Administration (FDA) for this indication (see Table 34.1 for available hormone therapy formulations). Although standard doses are usually effective, younger women and those with recent oophorectomy may require higher doses. Healthy, nonsmoking women in the perimenopausal transition who are experiencing bothersome hot ﬂashes but still menstruating may benefit from oral contraceptives. The supraphysiologic doses of estrogens and progestins in oral contraceptives effectively treat vasomotor symptoms and provide cycle control. Low-dose estrogen therapy Table 34.1 Hormone Therapy Options Table 34.1 Continued 17β-estradiol (E) + levonorgestrel (P) Climara Pro 0.045 mg E + 0.0015 mg P once weekly

Adult-onset hypogonadotropic hypogonadism caused by aberrant expression of aromatase in an adrenocortical adenocarcinoma.

Estrogen-secreting adrenal cancers are extremely rare, with feminizing symptoms attributed to aromatase expression in the adrenal tumor. We describe a case of hypogonadotropic hypogonadism as a consequence of aberrant aromatase expression in a patient with adrenocortical adenocarcinoma. A 54 year-old man presented with a two month history of gynecomastia and reduced libido. Endocrine biochemistry at presentation showed hypogonadotropic hypogonadism (LH 2.4 U/L, FSH <1.0 IU/L, testosterone 2.8 nmol/L) with increased serum estrone (E(1), 821 pmol/L) and estradiol (E(2), 797 pmol/L) and subclinical ACTH-independent hypercortisolism (serum cortisol post 1mg overnight dexamethasone suppression test, 291 nmol/L). A right adrenal mass was identified on CT scanning and the patient underwent an open adrenalectomy. Post-operative evaluation showed normalization of serum levels of E(1) (95 pmol/L), E(2 )(109 pmol/L), testosterone (11.4 nmol/L), LH (4.1 U/L) and FSH (5.9 IU/L), and of cortisol dynamics. Immunohistochemistry of the adrenal cancer confirmed aberrant expression of aromatase in most, although not all, carcinoma cells. Transcripts associated with utilization of promoters II, I.1 and I.3 were prominently represented in the tumor aromatase mRNA. This case highlights that clinical features of feminizing adrenocortical carcinomas can be secondary to estrogen production by aberrantly transcribed and translated aromatase within the tumor. Even in males, gonadotropin secretion is subject to predominantly estrogen-mediated feedback-inhibition. The diagnosis of adrenocortical adenocarcinoma should be considered in men presenting with low testosterone and gonadotropins, particularly in the presence of feminizing features.

[Effects of various contraceptives on laboratory parameters in diagnosis of thyroid gland function with special reference to the free hormones FT4 and FT3].

The effect of different oral contraceptives with an estrogen content of 30-50 micrograms ethinyloestradiol on thyroid hormones and the binding protein TBG was investigated and quantified for 200 women. The sera of 220 normal persons were analysed to get normal values for T3, T4, FT4, Ft3, TBG and TSH. Under the influence of antiovulatory hormone treatment the thyroxin binding globulin increased to values above 32 mg/l in 65% of all euthyroid women. The median for T4 changed from 97 to 120 nmol/l, respectively from 2.3 to 2.8 nmol/l for T3. We think the combination of TSH, FT4 and T3 to be the best analytical tool for differential diagnosis of hyperthyreose. The FT4 level was nearly independent of variations in TBG concentration, so we can accept the normal range from 10-28 pmol/l for patients with contraceptives as well. In 16% of these euthyroid women the T3 level proved to be in the hyperthyroid range with values above 3.6 nmol/l. The FT3 determination is stronger influenced by protein changes caused by oestrogens than FT4 and should not be accepted as a favourite parameter for patients with oral contraceptives.

Progestogen (medication)

In contrast to progestogen-only birth control, the addition of progestins to oral estrogen therapy, including in combined birth control pills and menopausal hormone therapy, is associated with a higher risk of VTE than with oral estrogen therapy alone. The risk of VTE is increased by about 2-fold or less with such regimens in menopausal hormone therapy and by 2- to 4-fold with combined birth control pills containing ethinylestradiol, both relative to non-use. In contrast to oral estrogen therapy, parenteral estradiol, such as with transdermal estradiol, is not associated with a higher risk of VTE. This is likely due to its lack of first-pass effect in the liver. Research is mixed on whether addition of progestins to transdermal estradiol is associated with a greater risk of VTE, with some studies finding no increase in risk and others finding higher risk. Unlike the case of transdermal estradiol, VTE risk is not lower with ethinylestradiol-containing contraceptive vaginal rings and

Effect of hormonal replacement therapy on autonomic regulation of the heart.

Increased incidence of cardiovascular diseases frequently reported in postmenopausal women may follow disturbed activity of cardiac autonomic nervous system (cANS). Our purpose was to evaluate the influence of continuous combined hormonal replacement therapy (ccHRT) on cANS reflected by parameters of heart rate variability (HRV). Thirty four healthy postmenopausal women aged 56+/-6 years (7+/-4 years after last menorrhoea) were divided into 2 equal groups--women receiving ccHRT (serum estradiol--81+/-75 ng/l, FSH--45+/-27 IU/l) and control group (serum estradiol--31+/-45 ng/l, FSH--74+/-32 IU/l). The ccHRT women have been receiving daily 50 mg of 17beta-estradiol (Oesclim 50, Fournier) in transcutaneous depot and 5 mg of oral progesterone (Duphaston, Solway Pharma) for recent 1.4+/-0.6 years. All recordings began at 8.00 a.m. and were carried out in supine position and resting conditions (room temperature 24 degrees C). The protocol applied consisted of 5 min. of resting ECG recording, 5 min. of deep breathing (DB) test, 6 min of sham feeding (SF) and 5 min. of ECG recording after SF. Analysis of the resting HRV didn't reveal any significant differences between the compared groups. In the control group during DB increases of mean LF (455+/-500 vs. 1381+/-1540; p<0.001) and LF/HF (1.5+/-1.1 vs. 5.4+/-4.3; p=0.002) ratio were observed. No influence of SF on HRV was noticed in this group. In the ccHRT women significant increases of mean LF (189+/-125 vs. 728+/-929; p=0.02) and LF/HF ratio (3.1+/-4.8 vs. 9+/-7.3; p=0.002) were observed during DB. SF revealed significant increases of mean RR (841+/-92 vs. 918+/-82; p<0.001), SDNN (35+/-14 vs. 43+/-20; p=0.02), LF (189+/-125 vs. 372+/-434; p=0.03) and HF (150+/-133 vs. 300+/-332; p=0.01). Our results revealed increased reactivity of the HRV parameters to vagal stimulation by DB and SF in the postmenopausal women receiving ccHRT that suggests increased activity of cANS in the analysed group. Application of ccHRT restores the premenopausal reactivity of cANS.

The pattern of gonadotropin and estradiol secretion in exaggerated thelarche.

To assess the dynamics of the pituitary-ovarian axis in exaggerated thelarche, defined as premature thelarche associated with signs of systemic estrogen effects (advanced bone age and/or growth acceleration) without progression to complete puberty. Seven girls (age < 2.5 years) with exaggerated thelarche, 6 girls with inactive pituitary-ovarian axis (premature adrenarche) and 21 girls with activated axis (central precocious puberty) had serum FSH, LH and E2 measured serially before and 1 to 24 h after gonadotropin-releasing hormone agonist (GnRHa) administration (leuprolide, 20 micrograms/kg sc), used as a test of combined pituitary-ovarian stimulation. Although girls in the exaggerated thelarche and adrenarche group had similar [mean (SEM)] baseline FSH [3.2 (0.9) vs 1.4 (0.3) IU/l], LH [0.36 (0.1) vs 0.27 (0.02) IU/l] and E2 [20 (1.2) vs 21 (2) pmol/l] concentrations, and similar peak post-GnRHa LH concentrations [5.5 (1.1) vs 2.4 (0.5) IU/l], girls with exaggerated thelarche achieved higher peak FSH [41 (9) vs 14 (3) IU/l, p < 0.01] and E2 [243 (40) vs 37 (6) pmol/l, p < 0.001] concentrations after GnRHa. In comparison to patients with exaggerated thelarche, girls with precocious puberty had higher (p < 0.01-0.001) baseline LH [3.6 (0.8) IU/l], baseline E2 [69(11) pmol/l], GnRHa-stimulated peak LH [68 (17) IU/l] and peak E2 [648 (58) pmol/l] concentrations, but similar FSH parameters. Girls with exaggerated thelarche exhibit substantial E2 secretory potential that can be demonstrated by GnRHa stimulation, is predominantly FSH-driven, and probably accounts for the manifestations of estrogen effect seen in these girls.

[Evaluation of selected X syndrome factors during hormonal replacement therapy].

Estrogen deficiency after menopause leads to characteristics changes in the hormonal profile, which may influence lipid carbohydrate and calcium-phosphate metabolism and some elements of homeostasis. To evaluate the influence of hormone replacement therapy with 2 mg estradiol valerate and 0,15 mg levonorgestrel on carbohydrate and lipid metabolism in women after menopause during 12 months of follow-up. We examined 101 women, mean age 52.9 +/- 4.6 years (range from 44 to 65). HRT was applied in 67 women whereas 34 women were without treatment. All of them had no carbohydrate disturbances. All women underwent clinical examination, and body mass index (BMI), fasting blood glucose, insulin, total cholesterol and triglycerides levels were obtained. At 1 and 2 hours after 75 g glucose challenge (75OGTT) glucose and insulin levels were obtained. During hormone replacement therapy all women noted release or significant decrease of climacteric symptoms. Total cholesterol level was decreased, whereas triglycerides did not change. After 12 months of treatment there was also a significant decrease of all factors relating to carbohydrate metabolism--fasting glucose and insulin, insulin/glucose ratio and area under glucose and insulin curves. In our study--after 6 months of follow-up fasting insulin level, area under glucose and insulin curves were increased whereas fasting blood glucose level remained unchanged. Among women without HRT there were no significant changes in selected lipid parameters and BMI. Triglyceride levels decreased (albeit insignificantly) but, total cholesterol levels did not change. After 12 months glucose level did not change, although other carbohydrate parameters were increased. 1) In the study group there was a statistically significant decrease in total cholesterol levels whereas triglycerides remained unchanged. 2) HRT we significantly decreased of insulin resistance and fasting blood glucose levels as compared with non-group HRT. 3) The present results indicate HRT-induced improvement of lipid and carbohydrate metabolism. 4) Long-term HRT is necessary to improve carbohydrate metabolism.

Human recombinant follicle-stimulating hormone induces growth of preovulatory follicles without concomitant increase in androgen and estrogen biosynthesis in a woman with isolated gonadotropin deficiency.

To evaluate the importance of luteinizing hormone (LH) for normal estrogen production and subsequent development of ovarian follicles, a woman with isolated gonadotropin deficiency (LH; 0.37 IU/L, FSH 1.2 IU/L) was monitored during recombinant human follicle-stimulating hormone (hFSHrec) administration with respect to ovarian follicular growth and steroid production. During the first week (75 IU/day hFSHrec im) a significant rise in serum FSH (4.9 IU/L) was observed in the absence of changes in serum estradiol (E2) concentrations (36-76 pmol/L). During the following five days 150 IU/day hFSHrec was administered resulting in a further increase of serum FSH levels (maximum 8.5 IU/L). Development of multiple follicles--maximum diameter 22 mm as observed by transvaginal sonography--emerged together with a minor rise in E2 levels (from 76 to 236 pmol/L) and with a minimal increase in endometrial thickness (below 6 mm). Six days following the last injection of hFSHrec, aspiration of 3 follicles (13, 15 and 18 mm) was performed and low intrafollicular androstenedione (AD) (less than 675 nmol/L) and E2 (less than 9400 pmol/L) concentrations as compared to normal follicles were found. These first data on hFSHrec administration in the human suggest that; a) FSH alone can induce growth of preovulatory follicles, b) follicle growth does occur in the presence of subnormal E2 levels, c) LH is needed for adequate AD biosynthesis as substrate for aromatase activity. This indicates that growth and steroidogenic granulosa cell activity may be differentially regulated.

[Rational hormonal diagnosis of secondary amenorrhea].

The usefulness of the guideline recommended in 1976 by the World Health Organization (WHO) for the differential diagnosis of ovarian sterility needs critical reevaluation, since it does not take into account new aspects such as the pulsatility of GnRH secretion, androgen excess, or thyroid disorders and other phenomena related to ovarian dysfunction. In order to demonstrate the relative frequency of such phenomena, the authors examined 183 women with secondary amenorrhea of more than three months' duration (mean +/- SD = 12.7 +/- 18.4 months). The endocrine status of these women was examined under standardized conditions in two clinical endocrinology units in the cities of Hamburg and Berlin. The percentages of abnormal hormonal data (greater than mean +/- SD + gray zone) were as follows: testosterone (T) 39.9%; DHEA sulfate (DS) 29.5%; prolactin (PRL) 18.0%; TSH 11.5%; FSH or LH 26.8%; estradiol (E2) 30.1%. Among 96 patients with increased T and/or DS (52.5% of all patients), 53 patients (55.2%) did not show any clinical signs of androgenization (hirsutism, acne). Retrospective evaluation of all data revealed that a stepwise diagnostic procedure would have resulted in the following cumulative percentages of hormonal abnormalities: (1) T = 39.9%; (2) +DS = 52.5%; (3) +PRL = 60.2%; (4) +LH/FSH = 82.0%; (5) +E2 = 91.2%; (6) +TSH = 92.3%. Only in 7.7% of all patients were all hormonal parameters within normal ranges. Individual case analysis showed that 52.5% of all patients had hyperandrogenemia, while 18% had hypothalamic amenorrhea without any other pathologic condition; 17.5% had hyperprolactinemia and 3.3% primary ovarian insufficiency. Another 4.9% had hypothyroidism only, while 1.1% had exclusively hyperthyroidism. Combined hormonal deviations were found in 24% of all patients. Considering the differential diagnosis of secondary amenorrhea from an economic point of view, one comes to the conclusion that direct and indirect expenditures are similar in magnitude, no matter whether one prefers a conventional stepwise procedure or a one-step hormonal analysis encompassing all potentially relevant hormones (DM 859.00 + 10 weeks waiting time vs. DM 827.50 + 1 week waiting time). Androgen excess is much more frequent than was believed; hirsutism and/or acne by no means necessarily occur in cases of androgen excess. Hyperprolactinemia is less frequent than hyperandrogenemia. Thyroid status should be evaluated in all women with functional amenorrhea. The stepwise diagnostic procedure as recommended by the WHO is time-consuming, complicated, and sometimes incomplete in the diagnostic work-up, with obvious potential disadvantages for therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Obstentrics_Williams

Phosphate (mg/dL) 2.5-4.3 3.1r-4.6 2.5-4.6 2.8-4.6 3,r26,r33,r39,r42 Potassium (mEq/L) 3.5-5.0 3.6-5.0 3.3-5.0 3.3-5.1 20,r26,r29,r39,r42,r63,r66 Protein, total (g/dL) 6.7-8.6 6.2-7.6 5.7-6.9 5.6-6.7 26,r29,r42 Sodium (mEq/L) 136-146 133-148 129-148 130-148 17,26,29,39,42,63,66 Urea nitrogen (mg/dL) 7-20 7-1r2 3-1r3 3-1r1 20,r39,r42 Uric acid (mg/dL) 2.5-5.6d 2.0-4.2 2.4-4.9 3.1r-6.3 17,r39,r42 Aldosterone (ng/dL) 2-9 6-104 9-104 15-101 21,r34,69 Angiotensin-converting 9-67 1-38 1-36 1-39 20, 54 Cortisol (19/dL) 0-25 7-1r9 10-42 12-50 42,r69 4-6 4-7 48,r49,r59 Thyroxine, total (T 4) 5.4-1r1.7 6.5-10.r1 7.5-1r0.3 6.3-9.7 29,r42 C-reactive protein (CRP) 0.2-3.0 Not reported 0.4-20.3 0.4-8.1 28 Dehydroepiandrosterone 1.3-6.8e 2.0-16.5 0.9-7.8 0.8-6.5 52 sulfate (DHEAS) Estradiol (pg/mU <20-443dJ 188--2497 1278-7192 6137-3460 1.3,52 Progesterone (ng/mL) <1-20d 8-48 99-342 13,n52 Prolactin (ng/mL) 0-20d 36-2n13 11n0-330 137-372 3,n13,n38,n49

Why perimenopausal women should consider to use a levonorgestrel intrauterine system.

The use of a levonorgestrel intrauterine system (LNG-IUS) is useful in preventing pregnancy and for the treatment of menstrual disturbances. A smooth or symptom-free transition to and through menopause is possible when LNG-IUS is combined with estrogen therapy. Unfortunately the majority of physicians are generally unaware of this usefulness combined hormonal therapy in the pre-, peri- and postmenopausal women. Based on long-term clinical experience with LNG-IUS in the form of Femilis®, 104 women where followed from the premenopause through the menopausal transition into the postmenopause. These perimenopausal women received supplemental 17 β-estradiol by gel or patch, or orally as estradiol valerate. Patients received one or two separate Femilis insertions at 5 year intervals. Main outcome measures included acceptability and continued use of the combined regimen for the treatment of climacteric symptoms and for prevention of cardiovascular disease, osteoporosis and other adverse effects caused by estrogen deprivation. The average age at insertion was 48 years (range 28-58) and the total duration of use was 137 months (range 80-161). The Femilis LNG-IUS was well tolerated as the number of removals for LNG-IUS-related reasons was low. The LNG-IUS was well retained in the uterine cavity as no expulsions were observed. Seven women were lost to follow-up. Eighty-six women (82%) opted for replacement of an LNG-IUS at expiry after 5 years and continued with the estrogen therapy. Intrauterine progestogen delivery for endometrial suppression in combination with estrogen therapy in the symptomatic perimenopausal women is highly practical as it combines the benefits of prevention of endometrial proliferation and treatment of menorrhagia and hyperplasia, if present. In addition, the contraceptive effect of locally administered LNG is highly desirable as many perimenopausal women run considerable risk of unintended pregnancy. For these reasons, the author views this regimen as one of the most effective, safest and best accepted route resulting in high patient compliance. It is important to convey this message to general practitioners as well as women.

[Effect of transdermal administration of 17-beta estradiol on the release of growth hormone by growth hormone liberating hormone (GH-RH-1-29) in climacteric women before and after treatment].

Great interest has sparked recently the role that plays the changes that the growth hormone undergoes in the menopausal woman, specially its involvement in the central nervous, cardiovascular, genitourinary, digestive and osteomuscular systems. To evaluate the influence of transdermal administration of 17-beta estradiol on growth hormone secretion in menopausal women before and after treatment under the stimulus of growth-hormonereleasing hormone (GH-RH). We studied 5 patients with a mean age of 51 +/- 4.1 yr. with clinical and biochemical evidence of menopause. Evolution time 5.4 +/- 4.61 (range: 1-13 yr.). We monitored the pulsatility of GH during the first 120 minutes and 3 hours after the administration of the GHRH-1-29-NH2, i.v. bolus (50 micrograms). There were obtained every 15 minutes for the determination of GH levels before and after the stimulus. Immediately thereafter hormone replacement therapy was initiated with transdermal beta-estradiol with 50 micrograms patches twice a week. Clinical evaluations and hormone dynamics with OHRH-1-29 were performed at baseline and at 1,3 and 6 months from the start of therapy as described previously. GH pulsatility before estrogen replacement therapy (ERT) in these 5 patients was: X: 0.48 +/- 0.22, 0.38 +/- 0.17, 0.45 +/- 0.25 and 0.29 (at baseline, 1, 3 and 6 months respectively) and 2.74 +/- o 1.21; 3.48 +/- 1.32 (p > 0.05) 4.91 +/- 1.57 (p < 0.05) and 6.04 +/- 1.69 (p < 0.05) (p in relation to baseline) post stimulus with GH-RH-1-29 at baseline 1, 3 and 6 months respectively after transdermal estrogen therapy. Gonadotrophins basal serum levels fall from X: 54.68 +/- 27 to 33.20 +/- 11.23 and 40.48 +/- 12 to 28.30 +/- 6.70 (FSH and LH respectively). Estradiol serum level were from 1.82 +/- 4.06 to 25.95 +/- 5.96 before and after treatment, respectively. These results demonstrate that transdermal estrogen therapy does not modify the pulsatility of growth hormone but it does increase the magnitude of response to the stimulus with GH-RH-1-29 proportional to the time of treatment. We consider that this tendency to increase the production of growth hormone could be explained by an endogenous deficit of growth hormone releasing hormone due to a number of factors including the lack of adequate estrogen serum levels in menopausal women. More investigations will be needed to support this hypothesis and to bring forth a new understanding of menopause and its treatment.

Combination immune checkpoint inhibitor therapy nivolumab and ipilimumab associated with multiple endocrinopathies.

Immune checkpoint inhibitors are the mainstay of treatment for advanced melanoma, and their use is being increasingly implicated in the development of autoimmune endocrinopathies. We present a case of a 52-year-old man with metastatic melanoma on combination nivolumab and ipilumimab therapy who developed concurrent hypophysitis, type 1 diabetes mellitus (T1DM) and diabetes insipidus. He presented prior to third cycle of combination treatment with a headache, myalgias and fatigue. Biochemistry and MRI pituitary confirmed anterior pituitary dysfunction with a TSH: 0.02 mU/L (0.5-5.5 mU/L), fT4: 5.2 pmol/L (11-22 pmol/L), fT3: 4.0 pmol/L (3.2-6.4 pmol/L), cortisol (12:00 h): <9 nmol/L (74-286 nmol/L), FSH: 0.7 IU/L (1.5-9.7 IU/L), LH: <0.1 IU/L (1.8-9.2 IU/L), PRL: 1 mIU/L (90-400 mIU/L), SHBG: 34 nmol/L (19-764 nmol/L) and total testosterone: <0.4 nmol/L (9.9-27.8 nmol/L). High-dose dexamethasone (8 mg) was administered followed by hydrocortisone, thyroxine and topical testosterone replacement. Two weeks post administration of the third cycle, he became unwell with lethargy, weight loss and nocturia. Central diabetes insipidus was diagnosed on the basis of symptoms and sodium of 149 mmol/L (135-145 mmol/L). Desmopressin nasal spray was instituted with symptom resolution and normalization of serum sodium. Three weeks later, he presented again polyuric and polydipsic. His capillary glucose was 20.8 mmol/L (ketones of 2.4 mmol), low C-peptide 0.05 nmol/L (0.4-1.5 nmol/L) and HbA1c of 7.7%. T1DM was suspected, and he was commenced on an insulin infusion with rapid symptom resolution. Insulin antibodies glutamic acid decarboxylase (GAD), insulin antibody-2 (IA-2) and zinc transporter-8 (ZnT8) were negative. A follow-up MRI pituitary revealed findings consistent with recovering autoimmune hypophysitis. Immunotherapy was discontinued based on the extent of these autoimmune endocrinopathies. The most effective regime for treatment of metastatic melanoma is combination immunotherapy with nivolumab and ipilumimab, and this therapy is associated with a high incidence of autoimmune endocrinopathies.Given the high prevalence of immune-related adverse events, the threshold for functional testing should be low.Traditional antibody testing may not be reliable to identify early-onset endocrinopathy.Routine screening pathways have yet to be adequately validated through clinical trials.

Laboratory criteria for menopause in women using oral contraceptives.

To evaluate laboratory criteria for menopause in women talking oral contraceptives (OC). Prospective, uncontrolled pilot study. San Francisco General Hospital, San Francisco, California, and Magee-Womens Hospital, Pittsburgh, Pennsylvania. Twenty-eight menopausal women. Fourteen menopausal women received triphasic 35 micrograms ethinyl E2 and 180-215-250 micrograms norgestimate, and 14 menopausal women received monophasic 30 micrograms ethinyl E2-150 micrograms desogestrel. Serum FSH, LH, and E2 levels were evaluated on days 14 and 28 (day 7 of the pill-free interval) of the third cycle of pills. Twelve women in each group completed the study. Fifteen (62.5%) subjects still had a serum FSH < 30 mIU/mL (30 IU/L) on the 7th day of the pill-free interval of the third pill package. All subjects had a serum FSH:LH ratio > 1 and 20 of 21 (95%) subjects had E2 < 20 pg/mL (73 pmol/L) at the end of the pill-free interval of the third cycle. Measuring FSH on the 7th day of the pill-free interval is not a sensitive test for menopause. Serum FSH:LH ratio > 1 or E2 < 20 pg/mL (73 pmol/L) on the 7th day of the pill-free interval may be a more appropriate marker of menopause in women using OC in the later reproductive years.

Alterations in sex steroids and gonadotropins in post-menopausal women subsequent to long-term mifepristone administration.

Long-term administration of progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) has been proposed as a novel hormonal therapy for various hormone dependent maladies. We studied the long-term endocrine effects of mifepristone on the kinetics of estradiol (E(2)) and its precursors, and on gonadotropin levels in five postmenopausal women treated for unresectable meningioma with mifepristone [200 mg/day] for at least 15 months. Serum samples were analyzed for LH, FSH and SHBG with fluoroimmunoassay; androstenedione (A), testosterone (T), estrone (E(1)) and E(2) were measured with radioimmunoassay (RIA). Serum levels of mifepristone were measured using both RIA and high performance-liquid chromatography (HPLC). Serum levels (mean +/- SD) of LH and FSH were suppressed from pretreatment values of 32 +/- 16 and 65 +/- 30 IU/l to 13 +/- 7 and 33 +/- 16 IU/l at 6 months (P < 0.05), respectively. Serum (mean +/- SD) A, T, E(1), and E(2) were increased from initial values of 6.9 +/- 0.9 nmol/l, 1.2 +/- 0.3 nmol/l, 77 +/- 25 pmol/l, and 29 +/- 14 pmol/l to 6 month values of 13.1 +/- 5.6 nmol/l, 1.8 +/- 0.6 nmol/l, 178 +/- 60 pmol/l, and 45 +/- 22 pmol/l (n.s.). The correlation coefficients between the levels of A, T, E(1), and E(2) were statistically significant, whereas the ratios of T/A, E(1)/A, E(2)/E(1), and E(2)/T remained unchanged. The levels of SHBG remained stable, and ranged from 48 +/- 10 to 65 +/- 9 nmol/l (mean +/- SD). Thus, prolonged mifepristone treatment marginally increased the serum levels of A, T, E(1) and E(2). These effects of mifepristone are likely due to its antiglucocorticoid effect and thus increased secretion of adrenal A. Serum levels of LH and FSH declined. The serum levels of gonadotropins and those of T, E(1) and E(2) were inversely, yet significantly, correlated. Therefore the decrease in LH and FSH might reflect the slightly increased levels of T, E(1) and E(2). However, the lack of change in SHBG and the low E(2) levels suggest that enhanced systemic estrogen effects are unlikely during long-term mifepristone treatment.

InternalMed_Harrison

no medication during which menstrual bleeding generally occurs. Two extended oral contraceptives are approved for use in the United States; Seasonale is a 3-month preparation with 84 days of active drug and 7 days of placebo, whereas Lybrel is a continuous preparation. Current doses of ethinyl estradiol range from 10 to 50 μg. However, indications for the 50-μg dose are rare, and the majority of formulations contain 30–35 μg of ethinyl estradiol. The reduced estrogen and progestin content in the secondand third-generation pills has decreased both side effects and risks associated with oral contraceptive use (Table 414-2). At the currently used doses, patients must be cautioned not to miss pills due to the potential for ovulation. Side effects, including breakthrough bleeding, amenorrhea, breast tenderness, and weight gain, often respond to a change in formulation. Even the lower dose oral contraceptives have been associated with an increased risk of cardiovascular disease (myocardial

Recombinant human follicle-stimulating hormone stimulates multiple follicular growth, but minimal estrogen production in gonadotropin-releasing hormone antagonist-treated monkeys: examining the role of luteinizing hormone in follicular development and steroidogenesis.

The two-cell theory predicts that follicular steroidogenesis requires the coordinate actions of both FSH and LH; however, the role of LH in follicular growth is less clear. The present study was designed to investigate the relative importance of LH and FSH in follicular growth and steroidogenesis. Cynomolgus monkeys were treated with a GnRH antagonist (antide; 3 mg/kg.day) for 20 days beginning in the midluteal phase of the menstrual cycle. After 10 days of antide administration, monkeys were injected with recombinant human FSH (rhFSH; 10 IU; n = 3), human menopausal gonadotropin (hMG; 10 IU; n = 3), or FSH plus 0.5 IU LH (n = 3) twice daily for 10 days. rhFSH stimulated multiple follicular development; however, peak serum estradiol levels were only 943 +/- 195 pmol/L. In contrast, monkeys treated with the same dose of hMG had significantly higher (P < 0.05) peak estradiol levels (6013 +/- 1322 pmol/L). The addition of 0.5 IU LH to the rhFSH treatment resulted in serum estradiol levels similar to those in monkeys treated with rhFSH only. Importantly, no differences in follicle number or size were evident among these treatment groups. Follicular fluid estradiol levels were consistent with serum levels (rhFSH, 187 +/- 11 nmol/L; hMG, 1531 +/- 173 nmol/L). Even larger proportional differences in follicular fluid androstenedione (rhFSH 13.6 +/- 1.4 nmol/L; hMG, 307 +/- 97.7 nmol/L) levels were found. The results in this LH-deficient primate model suggest that FSH alone is capable of stimulating ovarian follicular growth; however, the resulting follicles manifest minimal estradiol production, probably due to deficiencies in the LH-induced precursors to estradiol.

[Determination of serum free thyroxine: normal range, relation to the free thyroxine ratio and total thyroxine (author's transl)].

The validity of a commercially available f-T4 radioimmunoassay was investigated in 122 patients with different thyroid status. The normal range of f-T4 was 0.60-2.20 ng/dl in euthyroid patients from an endemic goiter area. No significant difference was found between normals and a group taking oral contraceptives (mean = 1.37 ng/dl vs. 1.45 nd/dl). In patients on thyroid hormone or antithyroid drug therapy, f-T4-values showed a better correlation with the results of an oral TRH-test than total T4 or the free thyroxine ratio (ETR). Specificity of ETR was better than that of f-T4. Sensitivity of f-T4 was higher in the group with negative TRH-test, but lower in hypothyroidism as compared to ETR. Determination of f-T4 by radioimmunoassay is a simple diagnostic procedure. Since f-T4 RIA is not influenced by changes in TBG-levels its use is particularly recommended in cases where such changes are to be expected such as estrogen application or gravidity.

[Hormone therapy in the 40-year-old woman].

Hormone replacement therapy is frequently prescribed in 40-year old women because of the hormonal changes which start to occur at this age. A progestogen-only treatment is often prescribed to restore the oestrogen/progestogen balance. This treatment alone can be sufficient on the therapeutic level as well as on the contraceptive level. However, in order to minimize the risks of such a treatment, a non-androgenic derivative must be chosen. There are no contra-indications for oral contraceptives in women who are over 40 years old on condition that the risk factors are not cumulated. Here also, it is advisable to use the lowest possible dose of steroids which has an adequate contraceptive action and enables a good cycle control. As for oestrogens, the minimum ethinyloestradiol dose must be sought. For the progesterone dose, a non-androgenic derivative should be chosen. The GnRH agonists may have some indications, but their exact place is yet to be defined.

Hormonal replacement regimens and bleeding.

Hormone replacement therapy may increase the quality of life of postmenopausal women. Any regimen need to offer long-term endometrial safety. It is a standard to consider the co-administration of a sequential progestogen when estrogen replacement should be initiated in non-hysterectomized women. It is almost impossible to decide which combination of an estrogen and a progestogen seems to be optimal as individual tolerance of HRT may very well limit acceptability despite metabolic benefits and proven endometrial safety of a given combination. Several combinations of oral and transdermal estradiol or conjugated equine estrogens, oral progestogens, transdermal norethisterone acetate and levonorgestrel, and intrauterine levonorgestrel may achieve endometrial safety. It is noteworthy that there is no uniform correlation between the timing of onset of bleeding induced by any sequential estrogen and progestogen replacement and a certain pattern of histology. Therefore, although it is likely, there is no absolute reassurance that regular bleeding on or after day 11 of progestogen administration rules out abnormal histopathology. Transvaginal sonography seems not to be of pivotal importance to screen asymptomatic women on replacement therapy for detection of serious abnormal endometrial findings such as hyperplasia and endometrial cancer. Continuous combined hormone replacement therapy or the use of tibolone may be an alternative in postmenopausal women, who do not want any uterine bleedings after menopause. However, spottings or bleedings most often occur at the beginning of treatment. Vaginal administration of estriol and estradiol for urogenital symptoms of estrogen deficiency may stimulate the endometrium unintentionally. Available data suggest that use of oral estriol may be associated with endometrial hyperplasia and endometrial carcinoma relatively more often compared to sequential HRT. Raloxifene, a benzothiophene derivative acting as a selective estrogen receptor modulator approved for prevention of vertebral osteoporosis, rarely causes uterine bleeding. There is no ideal therapy available to suit women looking for a permanently bleed-free hormonal replacement therapy today.

[Endometrial growth in continuous, estrogen substitution monotherapy with Estraderm TTS (0.05 mg/die) in 31 postmenopausal females].

To prevent hyperplasia and carcinoma of the endometrium during Estrogen Replacement Therapy (ERT), addition of progestogens once a month is considered mandatory. There is, however, no good scientific basis for this assumption. Since the addition of progestogens has several disadvantages, it is important to minimise the frequency of progestogen addition. Vaginosonography is a rather new technique, which has not yet been used for monitoring ERT. This study uses the growth of the endometrium, as it was measured by vaginosonography, as a parameter for stimulation of the endometrium by estrogens. ERT with Estraderm 50 twice a week was started in postmenopausal women. The endometrial thickness at the beginning was less than 3 millimeters. During estrogen treatment the endometrial thickness was determined every 6 to 10 weeks. As long as there was little or no increase during the estrogen treatment, no progestogen was added. Where there was a considerable growth, progestogen was added. With the use of vaginosonography, it is possible, to distinguish "fast growers" (women whose endometrium responded fast) from "slow growers".

Idiopathic primary ovarian insufficiency: a study of serial hormonal profiles to assess ovarian follicular activity.

Ovarian follicular activity in serial hormone profiles has been reported in up to 86% of patients with primary ovarian insufficiency (POI). In most of these studies, patients had a short duration of amenorrhea or irregular menstrual cycles which could influence the occurrence of spontaneous follicular activity. The aim was to study the incidence of follicular activity in serial hormonal profiles of women with spontaneous POI and amenorrhea of 1 year duration. This observational study involved 20 patients with spontaneous POI, amenorrhea of >1 year duration and normal karyotype. Serum measurements of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone, free T3, free T4, thyroid-stimulating hormone and anti-thyroperoxidase antibodies, taken in the absence of estrogen replacement, were followed by weekly measurements of serum E2, FSH, LH and progesterone for 1 month then monthly measurements for 2 months. Increases in serum E2 >184 pmol/l and serum progesterone >10 nmol/l were taken as evidence of follicular activity and ovulation, respectively. A rise in serum E2 >184 pmol/l was noted in 2/18 subjects [11.1%; 95% confidence interval (CI): 1.4-34.7%]. Though the corresponding serum FSH levels showed a decline, the values remained >40 IU/l. None of the subjects had serum progesterone levels >10 nmol/l, return of menses or pregnancy. Endogenous ovarian follicular function is intermittently present in only 11.1% of Asian Indian women with POI. However, the 95% CI (1.4-34.7%) was large due to a small sample size.

Effect of hypothyroidism on female reproductive hormones.

Objective was to evaluate reproductive hormones levels in hypothyroid women and impact of treatment on their levels. A total of 59 women with untreated primary hypothyroidism were included in this prospective study. Venous blood was taken at baseline and after euthyroidism was achieved for measuring serum free thyroxine, free triiodothyronine (FT3), thyroid stimulating hormone (TSH), prolactin (PRL), follicular stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone (T), and thyroid peroxidase antibody. Thirty-nine healthy women with regular menstrual cycles without any hormonal disturbances served as controls. The statistical analysis was performed using the Statistical Package for the Social Sciences Version 20 ([SPSS] IBM Corporation, Armonk, NY, USA). P < 0.05 was considered statistically significant. On an average at diagnosis cases have more serum TSH (mean [M] = 77.85; standard error [SE] = 11.72), PRL (M = 39.65; SE = 4.13) and less serum E2 (M = 50.00; SE = 2.25) and T (M = 35.40; SE = 2.31) than after achieving euthyroidism (M = 1.74; SE = 0.73), (M = 16.04; SE = 0.84), (M = 76.25; SE = 2.60), and (M = 40.29; SE = 2.27), respectively. This difference was statistically significant t (58) = 6.48, P <0.05; t (58) = 6.49, P < 0.05; t (58) = 12.47; P < 0.05; and t (58) = 2.04, P < 0.05; respectively. Although average serum FSH (M = 12.14; SE = 0.40) and LH (M = 5.89; SE = 0.27) were lower in cases at diagnosis than after achieving euthyroidism (M = 12.70; SE = 0.40), (M = 6.22; SE = 0.25), respectively, but these differences were statistically insignificant t (58) = 1.61, P = 0.11; t (58) = 1.11, P = 0.27, respectively. The study has demonstrated low E2 and T levels in hypothyroid women which were increased after achieving euthyroidism. Although average serum FSH and LH were increased in hypothyroid women after achieving euthyroidism but this difference was statistically insignificant.

Effect of long-term, high-dose estrogen treatment on prolactin levels: a retrospective analysis.

Exogenous estrogen administration causes prolactinoma formation in rats and there are anecdotal reports of estrogen treatment and prolactinoma formation in human transsexuals with male-to-female gender reassignment. It remains unclear whether chronic exposure to high-dose estrogen in women is linked with hyperprolactinemia. Aim The aim of this study was to determine whether high-dose, long-term subcutaneous estrogen treatment affected prolactin and gonadotropin levels. This was a retrospective, observational and descriptive analysis of 101 women treated for up to 15 years following a combined hysterectomy and oophorectomy. A total of 101 women who were receiving estradiol implants 50-100 mg 4-6 monthly, on demand for 5-15 years following abdominal hysterectomy and bilateral salphingo-oophorectomy were studied. The main outcome measures were levels of serum prolactin, follicle stimulating hormone (FSH) and luteinizing hormone (LH). Results The 101 patients received an average cumulative estrogen dose of (mean +/- SEM) 1239 +/- 12 mg per person, 18.96 +/- 1.2 mg/kg body weight, over a period of 5-15 years. The trough estradiol levels after withholding implants for 6 months were high (1047.9 +/- 52 pmol/l). Their average prolactin level of 88.88 +/- 9.2 mU/l was normal and their FSH (1.96 +/- 0.42 IU/l) and LH (2.97 +/- 0.88 IU/l) levels were relatively suppressed. These data are reassuring that, even in women exposed to very high doses of estrogen for a prolonged period of time, hyperprolactinemia is unlikely to occur.

[Estrogen-progestin contraception. Advantages of estrogen reduction].

Among the low dose oral contraceptives that is to say less than 50 mcg of ethinylestradiol per pill one must single out the pills made of a third generation progestagen (desogestrel, gestodene, norgestimate) from the others. The contraceptive efficacy (tested on the Pearl index) according to the files of government authorities visa (AMM) is equivalent for all the oral contraceptives whatever their composition (between 0 to 0.07 women year). The clinical tolerance of the low dose pills of the 3rd generation is comparable to that of the other low dose pills. Is there any advantage then in prescribing them? The most important advantage is the decrease of metabolic and vascular effects. The use of so-called third generation progestive, besides the beneficial effects an lipidic and glucidic metabolisms, has mainly enabled the decrease of the estrogen doses of progestagens. The ethinylestradiol is directly implicated in the risk of venous thrombosis: hemostasis the modifications are less important with 30 mcg than with 50, 20 than 30 mcg. Relying on theoretical arguments one could have estimated that minipills would lead to an insufficient ovarian slow down. These hypothesis are contradicted by recent studies from Falsetti and Benagiano who studied the rates of FSH and LH under minipills. This does not include the variability and the individual sensitiveness of the patients and as well the reason following which minipills would favor functional ovarian cysts, lies on the confusion made between a cyst and a 20 mm diameter follicule.(ABSTRACT TRUNCATED AT 250 WORDS)

Sex-hormone binding globulin as an indicator of the hepatic impacts of continuous combined hormone replacement regimens.

Nonoral administration of hormone replacement therapy avoids the first pass metabolism of steroids in the liver. We wanted to determine to what extent it has an effect on the serum concentrations of sex-hormone binding globulin and the free testosterone index. Postmenopausal women received 50 microg per day transdermal estradiol associated with the use of a levonorgestrel-releasing intrauterine device (20 women) or a daily oral dose of 2 mg of estradiol and 1 mg of norethisterone acetate (20 women) for 1 year. Eight women, five in the nonoral and three in the oral therapy group discontinued the study. Although serum sex-hormone binding globulin concentrations decreased in women receiving transdermal estradiol in combination with a levonorgestrel-releasing intrauterine device, the free testosterone index did not change significantly. In the continuous oral regimen, no significant changes in serum sex-hormone binding globulin or free testosterone index were observed. The free testosterone index, however, was significantly higher in the nonoral therapy group after 6 and 12 months of treatment than in the oral therapy group. Continuous progestin combined with continuous estrogen in oral and nonoral replacement therapy does not lead to a substantial androgenic excess in postmenopausal women. The intrauterine administration of levonorgestrel appears to have some hepatic effect.