Previous chapters have explored the definition, etiology, and health consequences of POI extensively. In summary, POI is generally defined as the cessation or disturbance of normal menses for 4 or more months, accompanied by elevated follicle-stimulating hormone (FSH) levels in the menopausal range (the exact menopausal range varies depending on the test run and assay). Similar to women with normal ovarian function undergoing menopause, women with POI have low estrogen levels and suffer resulting symptoms. The condition is chronic and affects 1 % of women under 40, with an unknown cause in roughly 90 % of patients [2]. For women and girls with the condition, myself included, it is a shocking and devastating diagnosis that requires lifelong management and, for many, forces changes to our life plans around creating a family [3]. Despite the similar indicators and menopausal-like symptoms that most women with POI experience, the condition is not “early menopause”: women and girls with POI may still ovulate occasionally, and an estimated 5–10 % conceive naturally [4].

Estrogen plays a critical role in the pubertal development of girls and in a woman’s overall health and well-being. Premature estrogen deficiency, no matter what the cause, has significant harmful health consequences, including increased rates of cardiovascular disease, stroke, total mortality, bone density loss, and vasomotor (when blood vessels constrict or dilate) symptoms. [5–13]. Patients with POI face all of these concerns.

To manage the health implications of estrogen deficiency, the American Society for Reproductive Medicine (ASRM) and most clinicians agree that women and girls with POI should receive a hormone replacement regimen [14–17]. Moreover, women with POI who I interviewed overwhelmingly feel positively about their choice to take hormone replacement and even recommend it to others with this diagnosis:

Hormone replacement is not a cure; rather, it is a palliative approach to treating POI’s sequelae and symptoms.

Estrogen deficiency can also result in a range of vasomotor (i.e., hot flashes and night sweats) and other physically uncomfortable and disruptive symptoms, some of the most common of which include insomnia and sleep disruption, mood changes, and tissue atrophy in the vulvovaginal region resulting in pain during sex [12, 13]. These symptoms are commonly experienced by women with POI, similar to women in menopause, and can be improved with HRT [13, 21].

According to the women I interviewed, the immediately noticeable vasomotor symptoms are the number one reason cited for starting and adhering to a hormone replacement regimen: HRT provides relief of hot flashes and night sweats within a matter of a few months. Michelle commented, “The hot flashes were becoming unbearable. I was having really bad night sweats [and] a hard time sleeping so I figured I would try anything to help get rid of it. It took two to three months for all of the symptoms to go away.” Sarah shared a similar experience, “The big thing was the hot flashes. It was to the point where it was affecting my work and my ability to cope… I just wanted that to end. That was the primary [driver] in terms of starting the conversation [about HRT].”

Notably, low estrogen levels reduce vaginal blood flow, causing tissue atrophy and leading to diminished lubrication and painful intercourse [13]. Studies of postmenopausal women have shown that both lowered vaginal blood flow and lubrication can be reversed by taking estrogens, including a low-dose estrogen transdermal skin patch [13, 22–24]. If relief of vasomotor symptoms is the number one reason to be grateful for HRT, relief of vaginal dryness is number two. Bobbi explained, “I felt aged, like I got old fast. Things started to slow down…I noticed a difference [with HRT]. Not right away, a couple of months into it. I felt like I was back to my 25-year old self.” Overall, sexual function and the impact of HRT in women with POI reveal a more nuanced story, addressed in a further section of this chapter.

In addition to low serum estradiol levels, women with POI also have reduced testosterone levels compared to controls [25]. There is conflicting evidence for the use of testosterone in women with POI, or for any woman, and testosterone augmentation to hormone therapy is not generally recommended. Testosterone has not been found to further benefit bone mineral density in women with POI [26]. Nor has testosterone been found to improve patient reports of quality of life or self-esteem, though mood was found to improve, albeit minimally [27]. However, ample evidence exists for the positive role that androgens (the group of sex hormones that include testosterone and that are the precursors to estrogen) play in affecting bone mass, mood, and libido in women [28].

Dehydroepiandrosterone (DHEA) , another type of androgen and a precursor of natural estrogens, is a supplement some women with POI take in the hopes of promoting ovulation and improving the chance of natural conception. Four of the seven interviewed women have taken it. In a 2013 study, two ovarian reserve markers (antral follicle count and total ovarian volume) improved in women with POI after 16 weeks of taking DHEA (25 mg three times per day), although there was no significant improvement in serum anti-müllerian hormone (AMH) or FSH levels [29]. Further, there are promising studies of the impact of DHEA combined with estrogen replacement to arrest bone loss and improve bone strength among young women with anorexia nervosa, another condition marked by estrogen deficiency [30, 31]. However, DHEA is not FDA regulated nor approved for HRT, and most clinicians caution against taking it until long-term safety trials are done. Given the inconclusiveness of potential benefits and risks of testosterone and DHEA supplementation, additional longer-term, randomized studies are warranted for women and girls with POI [21].

A number of hormone replacement options exist for clinicians and patients with POI that improve, or even restore, bone density, improve cardiovascular health, and lessen or alleviate other physical symptoms [26, 32]. Notwithstanding the choices available, there remains a significant need for additional research comparing different hormone replacement combinations, dosages, forms, and routes of administration to determine the safest and most efficacious regimens.

One of the most common types of HRT is a combination of estrogen and a progestogen; progestogen is a form of progesterone, the sex hormone that is secreted in the second half of the menstrual cycle after ovulation to prepare for and maintain pregnancy. The addition of a progestogen to the regimen helps to coordinate endometrial shedding and therefore reduces the chances of developing endometrial cancer and hyperplasia (a thickening of the uterine lining that can lead to cancer), a risk of taking estrogen on its own in women with intact uteruses [33–35].

Estrogen may be taken in many forms: transdermal patches, vaginal rings, pills, transmucosal creams, or gels. Using a skin patch or vaginal ring offers advantages over oral administration of pill form, mainly by delivering estradiol, which is the natural hormone that the ovaries make, without passing through the liver after absorption in the gut, thereby avoiding an increase in the production of proteins associated with heart disease and stroke [36]. In addition, the ring and patch release estradiol slowly and steadily into the bloodstream, rather than all at once [36]. Progestogen also comes in patch, cream, or pill form and can be taken cyclically (for 10–14 days every 30 or 60 days) or continuously. Taking progestogen continuously may avoid the need for regular menstrual bleeding to reduce the risk of endometrial cancer but not infrequently results in irregular and unpredictable breakthrough bleeding.

In addition to different forms, estrogen and progestogen can come from different sources, with different molecular structures. There is animal-derived, conjugated estrogen (e.g., Premarin, an estrogen made from pregnant mare’s urine, and the estrogen that one interviewee was on) and synthetic progestogens (e.g., medroxyprogesterone acetate). Alternatively, both estrogen and progestogen may be taken in bioidentical forms, produced from plant compounds in identical molecular structure as hormones women produce in their bodies [37]. Bioidentical estrogens include estrone (E1), estradiol (E2), and estriol (E3), and bioidentical progesterone is micronized (finely pulverized) progesterone [38]. Some patients and clinicians may prefer bioidentical hormones because these types most closely imitate the hormones a woman’s body produces naturally [37]. Some clinicians prescribe a mix: bioidentical estrogen and a concentrated progestogen. However, no evidence exists comparing the two types—bioidentical versus non-bioidentical—to determine overall supremacy of one type over the other [37].

Four of the seven women in the interview group are taking bioidentical estradiol transdermally accompanied by cyclic medroxyprogesterone acetate in oral pill form—the treatment of choice for many clinicians specializing in POI, including those at the NIH at which all of these women had at one time been referred. Estradiol is the most potent natural estrogen produced by the ovaries; its production increases during the first half of a woman’s cycle and peaks at ovulation. Medroxyprogesterone acetate is a synthetic form of progesterone. In this combination, estradiol is embedded within a patch that adheres to a spot on the skin below the waistline, prescribed at 100 μg per day continuously to reach physiologic levels of 50–100 pg/mL [38]. The administration of 10 mg per day of medroxyprogesterone acetate for the first twelve (12) days of each calendar month results in secretory endometrium that sheds after discontinuation and offers adequate protection against endometrial cancer [39]. The need for monthly cycles as compared to less frequent administration of a progestogen has not been well studied in women with POI.

Some women and their clinicians prefer doses and forms of replacement hormones that require compounding, in which ingredients are combined in a precise, customized potency and form. These regimens may include the bioidentical forms mentioned above, or other forms of hormones, e.g., those that are not generally available nor approved by federal drug regulators [37]. Only one woman in the interview group is taking compounded hormones and, in taking this alternative route with limited research support, has questions about her regimen’s efficacy, particularly on the implications for a natural pregnancy. (A 2013 Global Consensus Statement on Menopausal Hormone Therapy agreed to by various, international menopause societies, the Endocrine Society and the ASRM, does not recommend the use of custom-compounded bioidentical hormones [17]. In addition, in 2012 and 2013, a compounding pharmacy in New England was linked to multistate cases of fungal meningitis, resulting from injections of methylprednisolone acetate in patients with musculoskeletal pain [40].)

Some patients favor oral estrogen over a skin patch or vaginal ring [36]. In a study in the United Kingdom, of the 131 women with POI who chose HRT over other treatments (e.g., oral contraceptives), nearly 70 % chose to take estrogen orally rather than wear a patch; eighty-one (81) percent of women in the study age 40 and under and 52 % of women over 40 chose the pill form [21]. Overall, younger women may prefer to take regimens that allow for a regular menses and that do not require external administration to more closely mimic a “normal” cycle and their peers taking oral contraceptives [41].

It is critical for providers to understand the differences between HRT options and the commonly prescribed combined oral contraceptive pill. The primary goal should not be to just restore menses, but rather educate patients around the range of health implications of POI and empower them in their therapy choices. One internist told me to “just go back on the pill” to restore my periods. Oral contraceptives have higher doses of a synthetic estrogen than needed for physiologic replacement in women and girls with POI, yet estrogen doses in HRT are not high enough to prevent pregnancy [36]. Further, even in women and adolescents who do not wish to become pregnant, oral contraceptives may offer less effective prevention as compared to women without POI taking them especially if utilizing the 7-day pill-free week; barrier methods or an intrauterine device may be preferable [36, 42].

If a woman wishes to leave open the possibility of a natural pregnancy, she should choose a cyclical hormone regimen, simulating the changes in estrogen and progestin levels that occur when ovaries function normally [36]. Women with POI experience occasional ovarian function, with an estimated 4 % possibility of ovulating in any month [43]. Estradiol administration lowers follicle-stimulating hormone (FSH), and in up to 50 % of women with POI, transdermal estradiol has been shown to also achieve normal serum luteinizing hormone (LH) levels, despite the fact that LH is chronically high in women with POI [38]. The LH surge at mid-cycle causes the follicle to rupture, releasing the egg and causing a corpus luteum to develop. Theoretically, lowering LH levels in women with POI may improve follicle function though neither transdermal estradiol nor any other HRT has been proven to increase ovulation [38].

So, what hormone replacement option to choose? In consultation with her clinician, a woman should choose the form that best suits her, considering bone age, chronological age, symptoms, and any psychological or social factors [44]. A woman with POI should develop an ongoing individualized monitoring plan for HRT in consultation with her clinician, which may include occasional bone scans and hormone panels [45].

While one size of hormone replacement does not fit all women, there is significant evidence supporting estrogen therapy to increase bone mass and prevent bone loss. In an effort to “identify optimal hormone replacement therapy for women with POI,” Popat et al. found that patients on a regimen of 100 μg per day estradiol patch and 10 mg of medroxyprogesterone acetate for each of the first 12 days of a month restored bone density in the femoral neck and lumbar spine to normal in women with POI over the course of 3 years [26]. In addition to the hormone regimen, women took 520 mg of calcium carbonate two times per day.

A smaller scale, shorter duration study found increased bone formation and decreased bone resorption with physiological hormone replacement in patients with POI through transdermal estradiol and oral progestin therapy compared to an oral contraceptive (monophasic ethinyl estradiol and norethisterone) [46]. These authors conclude that “the type and profile of hormone replacement are critical and can have considerable effects on the bone health of women with [POI].”([46], p. 713) (An earlier study by this group concluded this same HRT offered beneficial cardiovascular impacts, including lower blood pressure and better renal function, compared to an oral contraceptive in women with POI [32].) In sum, there is emerging evidence arguing against the use of oral contraceptives as a form of HRT for young women with POI.

Thus, systemic HRT, in conjunction with adequate vitamin D and calcium and regular weight-bearing exercise, has been shown to prevent bone density loss and even to restore BMD to normal in women with POI [26]. All of these factors may be controlled to some extent by the patient and her clinician and can enhance bone health [47]. A greater than 1-year delay in diagnosis of POI, low vitamin D levels, smoking, noncompliance with HRT, inadequate calcium intake, and lack of regular exercise all increase the risk of reduced bone density in women with POI [47]. African-American and Asian women were more likely to experience these associated, modifiable risk factors and have been observed to have lower bone density than white women with POI [47]. One review found that women with POI are twice as likely to have reduced BMD when there is a greater than 1-year delay in diagnosis from the onset of symptoms [21].

After two and one-half years on HRT, while exercising regularly and taking calcium and vitamin D supplements, my bone density increased. I felt overjoyed and empowered by this outcome, which confirmed for me that these behavioral changes would directly enhance my health. Since an initial baseline DEXA scan found osteopenia, I have had regular scans roughly every 2 years. There is confusion among the women in the interview group about the recommended frequency of bone scans; if bone density is normal at baseline and a woman is on HRT, there is likely no need for another measurement until age 65, as generally recommended [48]. If the baseline scan shows signs of osteoporosis, more regular scans are warranted.

Research to date suggests the benefits of HRT in women and girls with POI outweigh its potential risks. The reality is no long-term studies exist to evaluate the risks of hormone replacement in women and girls with POI. More research is needed, including the potential implications for cancer risk, cognitive function, and mood.

The groundbreaking Women’s Health Initiative study and the resulting attention it received have led women, including those with POI, to worry about the possibly harmful effects of HRT [49]. It is critical that women know the Women’s Health Initiative study included only healthy postmenopausal women aged 50–79 (the average age was 63, much older than patients diagnosed with POI) who received combined estrogen and progesterone orally [50]. The HRT regimen described above (transdermal estradiol and progestogen) for women with POI aims to achieve normal physiologic levels for young women, with delivery of estradiol occurring transdermally or with an estradiol vaginal ring, not orally. I use the term HRT when I refer to treating young women with POI because these women are replacing hormones they are missing. That is not the case for women who enter menopause within the normal age range. For these women, the proper term is “hormone therapy,” a regimen under which exposure to ovarian hormones is extended beyond the normal occurrence, not replaced.

There is a growing body of research into the cognitive implications of hormone therapy on women in menopause, but to date its potentially protective or even aversive influences on mood, depression and anxiety, and memory in women in menopause remain unclear. A 2014 review of existing observational and clinical trials of hormone therapy in women in menopause found conflicting findings on cognitive function and mood, owing to significant inconsistencies among the studies; however, transdermal estradiol and progesterone are generally found to benefit cognitive function and mood, when initiated at the time of menopause [51]. A review of 35 neuroimaging studies on menopause and hormone therapy in 2014 concluded estrogen-only and estrogen-progestin therapies alter brain activation patterns, but the implications of the alterations on functioning and emotional processing remain largely unknown, especially for women with POI [52].

Dry eyes may also be connected to estrogen deficiency. A 2004 study by Smith et al. found that about 20 % of women with POI have dry eye syndrome and ocular-surface disease, a greater prevalence than women in an age-matched control group [53]. However, any beneficial impact of hormone replacement on alleviating dry eyes has not been proven. If a woman with POI experiences dry eyes, she should visit an ophthalmologist [14].

There are women with POI for whom HRT would not generally be recommended. Any woman who has had breast or endometrial cancer, heart disease, a history of blood clots, or liver disease ought to discuss with her clinician whether HRT is appropriate [54]. The choice of how hormone replacement gets administered may override whether some of these conditions, e.g., liver disease, are contraindicated. Administering estradiol transdermally (skin patch) or vaginally (tablet, cream, or ring) may be appropriate in certain circumstances when oral estrogen is contraindicated. If a woman has one of these disorders, she should discuss her particular situation with a clinician well versed in how to adapt HRT to her condition.

Women should avoid smoking while on HRT. Smoking has been linked to increased rates of osteoporosis, and studies indicate that women who smoke regularly have lower estrogen levels than women who do not smoke [55]. Mueck and Seeger conclude that women who continue to smoke on HRT should only use transdermal estradiol given the implications of the Women’s Health Initiative study [56].

Feelings of devastation, confusion, and shock commonly set in for women upon first hearing the diagnosis of POI [3, 21]. Given that response, the initial discussion with one’s clinician is critical in setting the stage for successful delivery of and compliance with HRT treatments. Unfortunately, too many women report these conversations are not long enough, lack in empathy, and do not lead to thorough follow-up [3]. Referral to a subspecialist with experience treating women with POI, such as a reproductive endocrinologist, may be appropriate in such situations.

Many women with POI struggle with diminished emotional well-being. Qualitative and quantitative research has shown that depression and anxiety are more pervasive in women with POI relative to women with normal functioning ovaries [57]. These experiences of diminished well-being are linked to uncertainty around the condition and stigmatization around infertility [58]. There is hope, however. Clinicians who convey a POI diagnosis have a variety of “best practices” available to help manage the response and reduce potentially harmful emotional and psychological impacts. These tools include providing thorough and accurate information to reduce uncertainty and limit feelings of stigmatization, spending ample in-person time with diagnosed patients, assisting women in redefining their family-building goals or in developing other meaningful plans, and encouraging them to sustain a sense of life purpose [3, 57].

Many women find out about the need to go on HRT at the time of their diagnosis—70 % of patients recalled their clinicians discussing a plan for hormone replacement in a 2005 observational study of 100 women with POI [3]. Similar tools and suggestions for effective communication of a diagnosis of POI also likely apply to the discussion around HRT. Sarah shared the disturbing story of how she initially came to learn about HRT: “The endocrinologist who told me said, ‘Oh, now you will be taking hormone replacement therapy. You have to do it because, if you don’t, your bones will fall apart.’ It was not as if I had a choice. I said ok.” Had Sarah’s clinician used the tools described above, she may have been left feeling cared for and empowered, rather than scared and trapped. From a patient perspective, this initial discussion around systemic HRT is a critical component to our overall sense of how POI will impact our lives, often for decades to come.

It is also critical for the clinician and the patient to work together over the duration of treatment to understand how HRT relates to the patient’s overall circumstances, self-perception, and life goals. Such a mutual understanding will increase the chance the patient will start HRT and comply with her regimen. I draw this conclusion from my own experience, along with the experience of the women I interviewed who have delayed or not fully complied with a hormone replacement regimen. Two women, Golie and Erika, shared that they delayed going on HRT, both for nearly a year. Golie explained her reasoning, “Initially I was very hesitant. I just didn’t want to take any medication, and I was in denial. I thought maybe by changing my diet, changing my stress levels, dealing with this emotionally, that maybe I could control my body to get the hormones back in balance… Another reason that I was scared to get on it is because I didn’t understand fully if it would reduce my chance of pregnancy.” Erika echoed that sense of trying to control, “I was fighting. I was trying to fix [my body].” And, in hindsight, Golie relays, “I wish I would have gotten on sooner. I wouldn’t have had to deal with the hot flashes [and] mood swings…I was miserable, and if I could have avoided that, I would have had a better quality of life those years, which were some of the worst of my life.”

Compliance is an issue even for women who may have started HRT as soon as it was prescribed, as it was for me. I used to cut my estradiol patch in half, hoping that I was taking the bare minimum of what I needed to protect my overall health. No evidence exists for the efficacy of that approach. Another woman reported stopping the progestogen cycle as soon as she started to bleed. There is no evidence for this approach either; in fact, Rebar recommends regular transvaginal ultrasounds if lower doses of progestogen are taken to ensure there are no signs of endometrial hyperplasia [15]. One study looked at compliance with hormone replacement in women requiring HRT after surgical menopause and concluded that compliance was high [59]; however, these finding may not apply to women with POI from other causes.