Clinical management of androgen excess and defect in women.

INTRODUCTION: Hyperandrogenism and hypoandrogenism are complex disorders involving multiple-organ systems. While androgen excess is a well-characterized condition, androgen deficiency still needs diagnostic criteria, as there are no specific cutoffs. AREAS COVERED: We highlight the most recent findings on the role of androgens in female pathophysiology, investigating clinically relevant conditions of androgen insufficiency or excess throughout a woman's life, and their possible therapeutic management. EXPERT OPINION: Combined oral contraceptives (COCs) should be considered as first-line therapy for the management of menstrual irregularity and/or clinical hyperandrogenism in adolescents with a clear diagnosis of polycystic ovary syndrome (PCOS). There are limited evidence-based data regarding specific types or doses of COCs for management of PCOS in women; however, the lowest effective estrogen dose should be considered for treatment. Despite evidence regarding safety, efficacy, and clinical use, testosterone therapy has not been approved for women by most regulatory agencies for treatment of hypoactive sexual desire disorder (HSDD). The long-term safety for treatments with testosterone is still to be evaluated, and this review highlights the need for more research in this area.

Revisiting the physiological role of androgens in women.

INTRODUCTION: Extensive research underlines the critical functions of androgens in females. Nevertheless, the precise mechanisms of their action are poorly understood. Here, we review the existing literature regarding the physiological role of androgens in women throughout life. AREAS COVERED: Several studies show that androgen receptors (ARs) are broadly expressed in numerous female tissues. They are essential for many physiological processes, including reproductive, sexual, cardiovascular, bone, muscle, and brain health. They are also involved in adipose tissue and liver function. Androgen levels change with the menstrual cycle and decrease in the first decades of life, independently of menopause. EXPERT OPINION: To date, studies are limited by including small numbers of women, the difficulty of dosing androgens, and their cyclical variations. In particular, whether androgens play any significant role in regulating the establishment of pregnancy is poorly understood. The neural functions of ARs have also been investigated less thoroughly, although it is expressed at high levels in brain structures. Moreover, the mechanism underlying the decline of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) with age is unclear. Other factors, including estrogen's effect on adrenal androgen production, reciprocal regulation of ARs, and non-classical effects of androgens, remain to be determined.

The use of different doses levonorgestrel-releasing intrauterine system (LNG-IUS): real-world data from a multicenter Italian study.

PURPOSE: Current research fails to adequately inform about the differential use of available levonorgestrel-releasing intrauterine systems (LNG-IUSs) in real life. Aim of our study was to compare the characteristics, satisfaction, continuation rates, and adverse effects between users of the high-dose LNG-IUS (52 mg) and of the low dose LNG-IUS (13.5 mg and 19.5 mg). MATERIALS AND METHODS: A prospective cohort study was performed in two Services for Family Planning in normal menstruating women with the inclusion of all new prescriptions of LNG-IUS for contraception. Women were followed for a mean of 9.1 ± 2.6 months after placement. RESULTS: 109 women (mean age of 39.8 ± 8.7 years old) were included, 69.7% using a high dose LNG-IUS and 30.3% using a low dose LNG-IUS. Women with a low dose LNG-IUS were significantly younger, thinner, more nulliparous, with fewer vaginal deliveries and C-sections, with a lower menstrual flow length and with more previous use of short-acting reversible contraceptives (p < 0.05). LNG-IUS continuation was similar and very high at the last follow-up: 100 vs. 94.7% in the low and high dose LNG-IUS groups, respectively (p = 0.18). Satisfaction with treatment at the end of the study was similar between different LNG-IUS doses (p = 0.85), with 78.9% being satisfied/very satisfied. Bleeding patterns were significantly different between the two LNG-IUS doses (p < 0.0001). Diagnosis of dysfunctional cysts was more frequent in women with high dose compared to low dose LNG-IUS (22.2 vs. 12.1%), albeit not significantly. CONCLUSIONS: We have shown a clear differential use of available LNG-IUS in clinical practice, both as baseline characteristics and as different outcomes, primarily for bleeding patterns. However, all these systems were associated with a very high rate of satisfaction and continuation.

Sonographic and clinical features of adenomyosis in women in "early" (18-35) and "advanced" (>35) reproductive ages.

BACKGROUND: Adenomyosis has been considered for a long time a condition of advanced reproductive age. Recently, imaging techniques have allowed its diagnosis in young women. The aim of our study was to compare adenomyosis in early (18-35) and advanced (>35) reproductive age (ERA vs. ARA). METHODS: Between May 2019 and October 2020, 928 consecutive women underwent transvaginal ultrasounds (TV-US) in our Department. We enrolled 134 women of reproductive age (18-55) presenting at least 2 US features of adenomyosis, according to the MUSA consensus. We compared the two reproductive age groups (ERA and ARA) about both clinical and US features of adenomyosis. RESULTS: Severe dysmenorrhea was more frequent in the ERA group (78.7% vs. 54.8%), while menorrhagia was more frequent in the ARA group (64.4% vs. 37.7%). At US, the ARA group had a higher frequency of altered junctional zone (67.1% vs. 39.3%), diffuse (76.7% vs. 39.3%) and severe adenomyosis (24.7% vs. 9.8%), and adenomyoma (16.4% vs. 1.6%). CONCLUSIONS: Adenomyosis may occur in young women, who present different clinical and sonographic features compared to older women. Young patients have a higher prevalence of severe dysmenorrhea and focal and mild adenomyosis at US, while older women present more frequently menorrhagia, and altered junctional zone, diffuse and severe adenomyosis at US. Early diagnosis in young women suffering from adenomyosis may help to interrupt the mechanisms that drive the development of adenomyosis, starting immediately the right treatment.

Effects of progestin-only contraceptives on the endometrium.

INTRODUCTION: The contraceptive activity of synthetic progestins is mediated through three basic mechanisms: (a) An anti-gonadotrophic action leading to the inhibition of ovulation; (b) Changes in cervical mucus characteristics that inhibit sperm penetration and (c) desynchronization of the endometrial picture necessary for implantation. AREAS COVERED: Mechanisms involved in the progestin-induced endometrium desynchronization are individually reviewed for each of the routes of administration and, whenever possible, by individual members of the various families of synthetic progestin derivatives. EXPERT OPINION: For contraceptive purposes, progestins are today administered through several routes: orally, as injections, subdermally and via the vagina or the uterine cavity. Given this variety of modalities, their effects may differ, depending on the route of administration, concentration reached at the level of the endometrium and the duration of use. These are characterized by inactivation of the endometrium. Progestin-only contraception provides a safe and effective control of fertility regulation, although, they are associated with the problem of endometrial break through bleeding that may lead to discontinuation. Unfortunately, in spite of a major research effort over two decades, there is not, as yet, an established long-term intervention available to manage bleeding irregularities, making mandatory a deeper understanding of the mechanisms involved is required.

Nexplanon Subdermal Implant: Assessment of Sexual Profile, Metabolism, and Bleeding in a Cohort of Italian Women.

OBJECTIVES: To evaluate the impact on metabolism, bleeding, and sexual function of Nexplanon, a subdermal implant. STUDY DESIGN: We recruited women (n=101) receiving the Nexplanon implant at two university centers in Italy between 2011 and 2016 into this prospective, observational, multicenter research trial. Participants completed the Interview for Ratings of Sexual Function (IRSF) and the Female Sexual Function Index (FSFI) questionnaires before and 3 and 6 months after the implant was inserted. In addition, all blood parameters were assessed at these visits. All women were given a menstrual diary card and a pictorial blood assessment chart to record daily any vaginal bleeding. RESULTS: The studied metabolic parameters remained in the normal range, showing no alarming modifications: minimal statistical reductions (in aspartate aminotransferase, alanine aminotransferase, total cholesterol, triglycerides, and activated partial thromboplastin time) and increases (in glucose and prothrombin activity) were observed. Changes in IRSF score over 6 months showed a significant increase in pleasure, personal initiative, orgasm, intensity of orgasm, and satisfaction, and a significant decrease in anxiety and discomfort. Mean Body Mass Index decreased, and the weekly frequency of sexual intercourse increased. CONCLUSIONS: Nexplanon showed not only a lower metabolic and bleeding impact, but also important positive effects on sexual function. It expands the range of possibilities for women, 38 and couples, in the modern concepts of sexual and reproductive wellbeing.

Uterine fibroids: an update on current and emerging medical treatment options.

Uterine fibroids are the most common gynecological disorder, classically requiring surgery when symptomatic. Although attempts at finding a nonsurgical cure date back to centuries, it is only around the middle of the last century that serious attempts at a medical treatment were carried out. Initially, both progestins and estrogen-progestin combinations have been utilized, although proof of their usefulness is lacking. A major step forward was achieved when peptide analogs of the GnRH were introduced, first those with superagonist properties and subsequently those acting as antagonists. Initially, the latter produced side effects preventing their routine utilization; eventually, this problem was overcome following the synthesis of cetrorelix. Because both types of analogs produce hypoestrogenism, their use is limited to a maximum of 6 months and, for this reason, today they are utilized as an adjuvant treatment before surgery with overall good results. Over the last decade, new, nonpeptidic, orally active GnRH-receptor blockers have also been synthesized. One of them, Elagolix, is in the early stages of testing in women with fibroids. Another fundamental development has been the utilization of the so-called selective progesterone receptor modulators, sometimes referred to as "antiprogestins". The first such compound to be applied to the long-term treatment of fibroids was Mifepristone; today, this compound is mostly used outside of Western Countries, where the substance of choice is Ulipristal acetate. Large clinical trials have proven the effectiveness of Ulipristal in the long-term medical therapy of fibroids, although some caution must be exercised because of the rare occurrence of liver complications. All selective progesterone receptor modulators produce unique endometrial changes that are today considered benign, reversible, and without negative consequences. In conclusion, long-term medical treatment of fibroids seems possible today, especially in premenopausal women.

Pharmacodynamics of combined estrogen-progestin oral contraceptives 3. Inhibition of ovulation.

INTRODUCTION: Following a historical overview, the ovulation-inhibiting effect of various orally administered estrogen-progestin combinations (combined oral contraceptives [COCs]) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens. Areas covered: Inhibition of ovulation with progestins alone; estrogens alone; various progestins in combination with ethinyl estradiol; various progestins in combination with natural estrogens (estradiol, estradiol valerate, and estetrol). Expert commentary: The original idea to achieve ovulation blockage through the administration of steroid hormones involved the use a progestogen (both progesterone and its synthetic homologous). The ability of a progestin to inhibit ovulation depends on the type of compound and on its dosage and a difference of more than 20-fold in activity exists between compounds utilized today in COCs. Initially, the estrogenic component was present only because it contaminated the first progestin utilized. It was soon found that an estrogen is necessary for proper cycle control. It was also found that the estrogen acts synergistically in inhibiting ovulation. For almost half a century, most COCs contained ethinyl estradiol. Today, also natural estrogens are being employed. Inhibition of ovulation was complete with all early high dose preparations. Decreasing dosage allowed some ovarian activity to occur, occasionally leading to a mature follicle. Even in this situation, defective corpus luteum formation assured contraceptive protection.

Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis.

INTRODUCTION: The pharmacodynamic effects of various combined oral estrogen-progestin combinations (COC) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens. Areas covered: Recent information on the effect of androgens, estrogens, progestins, as well as various COC combinations on the coagulation cascade will be reviewed aiming at providing an updated picture. The present article reviews hemostatic changes occurring during use of classic and modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), compared to classic compounds, such as levonorgestrel. Both pro- and anti-coagulatory effects of COC in healthy women are detailed and possible links with incidence of thromboembolic events are discussed. Expert commentary: Overall, the picture is reassuring: the use of natural estrogens and of new generation progestins has reduced pro-coagulatory changes in healthy subjects, although the observed differences in the risk of venous thromboembolism between second and third generation progestins is still incompletely understood. At the same time, there still is a need for large comparative and surveillance studies before firm conclusions can be drawn. At any rate, available evidence indicates that hemostatic effects of the newer COC, especially those utilizing natural estrogens, are minimal and often remain with the normal range.

Pharmacodynamics of combined estrogen-progestin oral contraceptives: 1. Effects on metabolism.

INTRODUCTION: The risk-benefit profile of any pharmacologic agent must be evaluated against risks connected with the events to be avoided. This is especially true in the case of hormonal contraception, not intended to combat a disease. Over the six decades during which their use has progressively expanded, the risk-benefit profile of combined oral contraceptives (COC) has substantially changed, with new combinations, dosages and mode of administration appearing on the market. Area covered: In a series of articles, recent information on the complex issue of COC risks and benefits will be reviewed in the hope of providing an updated picture. The present article reviews metabolic changes occurring during use of modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), often compared to classic compounds, such as levonorgestrel. Three categories of metabolic effects in healthy women are detailed: on carbohydrates, lipid and bone mineral content. Expert commentary: Overall, the picture is reassuring: the new generations of progestins are basically devoid of androgenic, estrogenic or glucocorticoid related side-effects. This should result in an improved safety profile, although past history teaches us that that large comparative and surveillance studies are required before firm conclusions can be drawn. At any rate, available evidence indicates that metabolic effects of third and fourth generation progestins, especially when they are combined with natural estrogens, are minimal and, if used in healthy women, should not cause concern.

An observational study of adherence to combined oral contraceptive regimens.

OBJECTIVE: To analyze adherence to an oral contraceptive (OC) regimen and correlate results to participants' socio-demographic and behavioral characteristics. METHODS: Women were prospectively enrolled and followed for 6 months. At enrollment, subjects were given a card for recording daily pill intake; its completion was checked at 6 months when women completed a self-administered questionnaire. RESULTS: Out of 755 eligible subjects, 704 agreed to participate; 402 women completed 6 months of recording of use of an OC and properly filled the questionnaire. Good adherence was reported by 64% of participants; 20.9% missed one pill and 14.9% missed more than one pill. Mean number of missed pills per subject was 0.59 and mean number of pills delayed for less than 24 h was 1.18. Best adherence to a COC regimen was associated with evening time intake (p = 0.0019). No statistically significant associations of adherence with socio-demographic characteristics were found. Age was only marginally associated with having missed at least one pill. CONCLUSION: In the present study, a lower number of missed pills were observed than previously reported, but the proportion of missed pills was similar. No association with specific subject characteristics that could serve as markers of increased risk of nonadherence was found.

Hypertension and early menopause after the use of assisted reproductive technologies in women aged 43 years or older: Long-term follow-up study.

AIM: The aim of this study was to investigate the long-term consequences to women's health and the onset of menopause in healthy women of advanced reproductive age who conceived by assisted reproductive technologies (ART). METHODS: Healthy women who conceived by ART (72) and controls (80) were selected among 320 women ≥ 43 years, who delivered between January 2010 and December 2011 in the Department of Gynecological and Obstetrical Sciences and Urological Sciences of "Sapienza" University of Rome. Body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and presence of hypertension and diabetes were analyzed at three days, six months, and three years after delivery. The onset of menopause was analyzed after three years. RESULTS: In the ART group, SBP, DBP and hypertension were higher at three days, six months, and three years after delivery. Menopausal age was significantly lower. CONCLUSION: The impact of ART in healthy women of advanced reproductive age in the years after delivery is not limited to the possible development of cardiovascular risk factors, such as hypertension, but can also influence the age of onset of menopause.

Emergency contraception: a survey of 1773 women.

OBJECTIVES: The aim of the study was to retrieve data on the characteristics and profile of women attending an emergency service (ES) to receive a prescription (mandatory until May 2015) for emergency contraception (EC). METHODS: In a retrospective study the following data were collected for all women requesting EC between January 2014 and June 2015: demographic characteristics, time between unprotected sexual intercourse (USI) and arrival at the ES, time between the last menstrual period and the USI, and type of EC prescribed. In a prospective study starting January 2015, a questionnaire was administered requesting the following information: reasons for requiring EC, previous EC use, source of knowledge about EC, prior contraception and age at first intercourse. RESULTS: During the whole study period, 1773 women requested EC: their mean age was 26.0 years; 78.5% were Italian; 91.5% were unmarried; 55.2% were still studying and 51.9% had high school education; 61.2% reached the ES within 12 h of the USI; and 42.4% had a USI during days 9-16 of their menstrual cycle. Levonorgestrel was prescribed in 81.4% of women and ulipristal acetate in 17.7%. In the prospective part of the study (382 women), the majority (57.9%) requested EC for condom rupture; 49.5% reported previous use of EC; and 41.6% received information on the subject through friends. The vast majority (83.8%) reported prior use of contraception; in 25.4% the reason for not using it was the absence of a relationship. CONCLUSION: An exact profile of women requesting EC can help women in their choice of permanent contraception, and help clinicians in counselling women on appropriate contraception.

Mechanism of Action of Ulipristal Acetate for Emergency Contraception: A Systematic Review.

Ulipristal acetate (UPA) is now recommended as first choice hormonal emergency contraception (EC), due to its higher efficacy and similar safety compared to Levonorgestrel - EC. Even though all trials demonstrated that the first mechanism of action is inhibition of ovulation, some authors still postulate that a post fertilization effect is also possible, raising the alert on medication and fostering the ethical debate. A Medline database search was performed in order to find recent articles related to UPA's effects on ovulation, on fallopian tube and on endometrium. We also analyzed the effects on sperm function and pregnancy. All studies conclude that UPA is effective in inhibition of ovulation even when administered shortly before LH peak. The effects on fallopian tube are unclear: according to some authors UPA inhibits ciliar beat through an agonistic effect on progesterone receptors, according to others it antagonizes the progesterone-induced ciliar beat decrease. Concerning the action on endometrium and on embryo implantation most of the studies concluded that low dose UPA used for EC has no significant effect on the decrease of endometrial thickness and on embryo's attachment, but these results are still matter of debate. Finally recent evidence suggests that UPA modulates human sperm functions while it has no effect on established pregnancy. To date the majority of the evidence concurs in excluding a post-fertilization effect of UPA, even though more studies are needed to clarify its mechanism of action.